The autophagy initiation complex is brought about via a highly ordered and stepwise assembly process. Two crucial signaling molecules, mTORC1 and AMPK, orchestrate this assembly by phosphorylating/dephosphorylating autophagy‐related proteins. Activation of Atg1 followed by recruitment of both Atg9 vesicles and the PI3K complex I to the PAS (phagophore assembly site) are particularly crucial steps in its formation. Ypt1, a small Rab GTPase in yeast cells, also plays an essential role in the formation of the autophagy initiation complex through multiple regulatory (...) pathways. In this review, our primary focus is to discuss how signaling molecules initiate the assembly of the autophagy initiation complex, and highlight the significant roles of Ypt1 in this process. We end by addressing issues that need future clarification. (shrink)

Microtubules are protein cylinders with functions in cell motility, signal sensing, cell organization, intracellular transport, and chromosome segregation. One of the key properties of microtubules is their dynamic architecture, allowing them to grow and shrink in length by adding or removing copies of their basic subunit, the heterodimer αβ‐tubulin. In higher eukaryotes, de novo assembly of microtubules from αβ‐tubulin is initiated by a 2 MDa multi‐subunit complex, the gamma‐tubulin ring complex (γ‐TuRC). For many years, the structure of the γ‐TuRC and (...) the function of its subunits remained enigmatic, although structural data from the much simpler yeast counterpart, the γ‐tubulin small complex (γ‐TuSC), were available. Two recent breakthroughs in the field, high‐resolution structural analysis and recombinant reconstitution of the complex, have revolutionized our knowledge about the architecture and function of the γ‐TuRC and will form the basis for addressing outstanding questions about biogenesis and regulation of this essential microtubule organizer. (shrink)

Molecular Revolution in BrazilFélix Guattari and Suely Rolniktranslated by Karel Clapshow and Brian HolmesYes, I believe that there is a multiple people, a people of mutants, a people of potentialities that appears and disappears, that is embodied in social, literary, and musical events.... I think that we're in a period of productivity, proliferation, creation, utterly fabulous revolutions from the viewpoint of this emergence of a people. That's molecular revolution: it isn't a slogan or a program, it's something that (...) I feel, that I live....--from Molecular Revolution in BrazilFollowing Brazil's first democratic election after two decades of military dictatorship, French philosopher Félix Guattari traveled through Brazil in 1982 with Brazilian psychoanalyst Suely Rolnik and discovered an exciting, new political vitality. In the infancy of its new republic, Brazil was moving against traditional hierarchies of control and totalitarian regimes and founding a revolution of ideas and politics. Molecular Revolution in Brazil documents the conversations, discussions, and debates that arose during the trip, including a dialogue between Guattari and Brazil's future President Luis Ignacia Lula da Silva, then a young gubernatorial candidate. Through these exchanges, Guattari cuts through to the shadowy practices of globalization gone awry and boldly charts a revolution in practice.Assembled and edited by Rolnik, Molecular Revolution in Brazil is organized thematically; aphoristic at times, it presents a lesser-known, more overtly political aspect of Guattari's work. Originally published in Brazil in 1986 as Micropolitica: Cartografias do desejo, the book became a crucial reference for political movements in Brazil in the 1980s and 1990s. It now provides English-speaking readers with an invaluable picture of the radical thought and optimism that lies at the root of Lula's Brazil. Félix Guattari, post-'68 French psychoanalyst and philosopher, is the author of Anti-Oedipus, The Anti-Oedipus Papers, 2006), and other books. Semiotext has published the first two volumes of his complete essays, Chaosophy and Soft Subversions, and will publish the final volume, Chaos and Complexity, in 2008. Suely Rolnik is a psychoanalyst, cultural critic, and curator who lives and works in São Paulo, Brazil. She was a close collaborator of Guattari during her exile in Paris from the military dictatorship in Brazil. (shrink)

Molecular Revolution in BrazilFélix Guattari and Suely Rolniktranslated by KarelClapshow and Brian HolmesYes, I believe that there is a multiple people, a people of mutants, apeople of potentialities that appears and disappears, that is embodied in social, literary, andmusical events.... I think that we're in a period of productivity, proliferation, creation, utterlyfabulous revolutions from the viewpoint of this emergence of a people. That's molecular revolution:it isn't a slogan or a program, it's something that I feel, that I live....--from (...) MolecularRevolution in BrazilFollowing Brazil's first democratic election after two decades of militarydictatorship, French philosopher Félix Guattari traveled through Brazil in 1982 with Brazilianpsychoanalyst Suely Rolnik and discovered an exciting, new political vitality. In the infancy of itsnew republic, Brazil was moving against traditional hierarchies of control and totalitarian regimesand founding a revolution of ideas and politics. Molecular Revolution in Brazil documents theconversations, discussions, and debates that arose during the trip, including a dialogue betweenGuattari and Brazil's future President Luis Ignacia Lula da Silva, then a young gubernatorialcandidate. Through these exchanges, Guattari cuts through to the shadowy practices of globalizationgone awry and boldly charts a revolution in practice.Assembled and edited by Rolnik, MolecularRevolution in Brazil is organized thematically; aphoristic at times, it presents a lesser-known,more overtly political aspect of Guattari's work. Originally published in Brazil in 1986 asMicropolitica: Cartografias do desejo, the book became a crucial reference for political movementsin Brazil in the 1980s and 1990s. It now provides English-speaking readers with an invaluablepicture of the radical thought and optimism that lies at the root of Lula's Brazil. Félix Guattari, post-'68 French psychoanalyst and philosopher, is the author of Anti-Oedipus, The Anti-Oedipus Papers, 2006), and other books. Semiotext haspublished the first two volumes of his complete essays, Chaosophy and Soft Subversions, and will publish the final volume, Chaos and Complexity, in 2008. Suely Rolnik is apsychoanalyst, cultural critic, and curator who lives and works in São Paulo, Brazil. She was aclose collaborator of Guattari during her exile in Paris from the military dictatorship inBrazil. (shrink)

The view is presented that extracellular architecture in plant cell walls results from an interplay between molecular self‐assembly and mechanical reorientation due to growth forces. A key initial self‐assembly step may involve hemicelluloses. It is suggested that hemicelluloses may self‐assemble into a helicoid via a cholesteric liquid crystalline phase; the detailed molecular structure of hemicelluloses (stiff backbone, bulky side chains, and the presence of asymmetric carbon atoms) is shown to be consistent with cholesteric requirements for such self‐assembly. Since (...) hemicelluloses are hydrogen‐bonded to the periphery of cellulose microfibrils, the cellulose could then itself become helicoidally arranged. Such ‘universal plywood’ structure is found in the walls of a wide variety of plants, and in several types of cell (including wood). The permanent effects of growth stresses on patterns seen in sections of helicoids are displayed by computer graphics plots, and the expected changes in stiffness are calculated. (shrink)

Molecular motor proteins, fueled by energy from ATP hydrolysis, move along actin filaments or microtubules, performing work in the cell. The kinesin microtubule motors transport vesicles or organelles, assemble bipolar spindles or depolymerize microtubules, functioning in basic cellular processes. The mechanism by which motor proteins convert energy from ATP hydrolysis into work is likely to differ in basic ways from man‐made machines. Several mechanical elements of the kinesin motors have now been tentatively identified, permitting researchers to begin to decipher (...) the mechanism of motor function. The force‐producing conformational changes of the motor and the means by which they are amplified are probably different for the plus‐ and minus‐end kinesin motors. BioEssays 25:1212–1219, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

An astonishingly diverse biomolecular circuitry orchestrates the functioning machinery underlying every living cell. These biomolecules and their circuits have been engineered not only for various industrial applications but also to perform other atypical functions that they were not evolved for—including computation. Various kinds of computational challenges, such as solving NP‐complete problems with many variables, logical computation, neural network operations, and cryptography, have all been attempted through this unconventional computing paradigm. In this review, we highlight key experiments across three different ‘‘eras’’ (...) of molecular computation, beginning with molecular solutions, transitioning to logic circuits and ultimately, more complex molecular networks. We also discuss a variety of applications of molecular computation, from solving NP‐hard problems to self‐assembled nanostructures for delivering molecules, and provide a glimpse into the exciting potential that molecular computing holds for the future. Also see the video abstract here: https://youtu.be/9Mw0K0vCSQw. (shrink)

Regulation of microtubule (MT) dynamics is essential for many cellular processes, but the machinery that controls MT dynamics remains poorly understood. MT plus‐end tracking proteins (+TIPs) are a set of MT‐associated proteins that dynamically track growing MT ends and are uniquely positioned to govern MT dynamics. +TIPs associate with each other in a complex array of inter‐ and intra‐molecular interactions known as the “+TIP network.” Why do so many +TIPs bind to other +TIPs? Typical answers include the ideas that (...) these interactions localize proteins where they are needed, deliver proteins to the cortex, and/or create regulatory pathways. We propose an additional and more mechanistic hypothesis: that +TIPs bind each other to create a superstructure that promotes MT assembly by constraining the structural fluctuations of the MT tip, thus acting as a polymerization chaperone. (shrink)

We present a molecular model of eukaryotic gene transcription. For the β‐globin locus, we hypothesise that a transcription machine composed of multiple RNA polymerase II (PolII) assembles using the locus control region as a foundation. Transcription and locus remodelling can be achieved by pulling DNA through this multi‐PolII ‘reading head’. Once a transcription complex is formed, it may engage an active gene in several rounds of transcription. Observed intergenic sense and antisense transcripts may be the result of PolII pulling (...) the DNA through the reading head whilst searching for the promoter of a gene. Support for this hypothesis is provided using various data from the literature. In the model, DNA is packed in a 30‐nm chromatin fibre, thus gene regulatory regions separated by kilobases are close in space. This, and the need to store transcription‐induced supercoiling, may explain why functionally interacting regions are often separated by many kilobases. (shrink)

Basement membranes are thin sheets of extracellular proteins situated in close contact with cells at various locations in the body. They have a great influence on tissue compartmentalization and cellular phenotypes from early embryonic development onwards. The major constituents of all basement membranes are collagen IV and laminin, which both exist as multiple isoforms and each form a huge irregular network by self assembly. These networks are connected by nidogen, which also binds to several other components (proteoglycans, fibulins). Basement membranes (...) are connected to cells by several receptors of the integrin family, which bind preferentially to laminins and collagen IV, and via some lectin‐type interactions. The formation of basement membranes requires cooperation between different cell types since nidogen, for example, is usually synthesized by cells other than those exposed to the basement membranes. Thus many molecular interactions, of variable affinities, determine the final shape of basement membranes and their preferred subanatomical localization. (shrink)

Together with microtubules and actin microfilaments, ∼11 nm wide intermediate filaments (IFs) constitute the integrated, dynamic filament network present in the cytoplasm of metazoan cells. This network is critically involved in division, motility and other cellular processes. While the structures of microtubules and microfilaments are known in atomic detail, IF architecture is presently much less understood. The elementary ‘building block’ of IFs is a highly elongated, rod‐like dimer based on an α‐helical coiled‐coil structure. Assembly of cytoplasmic IF proteins, such as (...) vimentin, begins with a lateral association of dimers into tetramers and gradually into the so‐called unit‐length filaments (ULFs). Subsequently ULFs start to anneal longitudinally, ultimately yielding mature IFs after a compaction step. For nuclear lamins, however, assembly starts with a head‐to‐tail association of dimers. Recently, X‐ray crystallographic data were obtained for several fragments of the vimentin dimer. Based on the dimer structure, molecular models of the tetramer and the entire filament are now a possibility. BioEssays 25:243–251, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Lately there has been a growing interest in evolutionary studies concerning how the regularities and patterns found in the living cell could have emerged spontaneously by way of self-assembly and self-organization. It is reasonable to postulate that the chemical compounds found in the primitive Earth would have mostly been very simple in nature, and would have been immersed in the natural dynamics of the physical world, some of which would have involved self-organization. It seems likely that some molecular processes (...) self-organized spontaneously into a hierarchy of complex behaviours. Our conceptual search herein reaches back to the time when prebiotic phenomena began to take shape. This was before the origin of life, so in this paper we hope to shed new light on some of the theoretical issues that surround the ways in which cellular organization might have evolved without the aid of replicated information. (shrink)

In mammalian cells, a complex network of signaling pathways tightly regulates a variety of cellular processes, such as proliferation and differentiation. New insights from one of the most‐important signaling cascades involved in oncogenesis, the Ras–Raf–MAPK pathway, suggest that the subcellular localisation and assembly of signaling modules of this pathway is crucial to control the biological response. This commonly requires membrane targeting events that are mediated by adaptor/scaffold proteins. Of particular interest is the translocation and complex formation of GTPase‐activating proteins (GAPs), (...) such as p120GAP, at the plasma membrane to inactivate Ras. Recent studies indicate that one member of the annexin family, annexin A6 acts as a targeting protein for p120GAP. This review discusses how annexin A6 modulates the involvement of negative regulators of the Ras–Raf–MAPK pathway contributing to Ras inactivation. BioEssays 28: 1211–1220, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

The type III secretion system (T3SS) is a specialized nanomachine that enables bacteria to secrete proteins in a specific order and directly deliver a specific set of them, collectively known as effectors, into eukaryotic organisms. The core structure of the T3SS is a syringe‐like apparatus composed of multiple building blocks, including both membrane‐associated and soluble proteins. The cytosolic components organize together in a chamber‐like structure known as the sorting platform (SP), responsible for recruiting, sorting, and initiating the substrates destined to (...) engage this secretion pathway. In this article, we provide an overview of recent findings on the SP's structure and function, with a particular focus on its assembly pathway. Furthermore, we discuss the molecular mechanisms behind the recruitment and hierarchical sorting of substrates by this cytosolic complex. Overall, the T3SS is a highly specialized and complex system that requires precise coordination to function properly. A deeper understanding of how the SP orchestrates T3S could enhance our comprehension of this complex nanomachine, which is central to the host‐pathogen interface, and could aid in the development of novel strategies to fight bacterial infections. (shrink)

A variety of leech homeobox genes have been identified by homology with genes that are known to bring about the regionalization and segmentation of the anteroposterior body axis in other organisms. Embryonic expression patterns suggest a number of interphyletic similarities in the way that these genes are utilized. However, several interesting differences have also been observed. In particular, transplantation experiments in the leech embryo have shown that axially aligned patterns of homeobox gene expression are not specified by a global pattern (...) of positional cues. Rather, the leech independently establishes anteroposterior patterns of gene expression in each of five discrete stem cell lineages, and these patterns are brought into their final alignment through a process of morphogenetic assembly. (shrink)

The establishment of a functional vascular system requires multiple complex steps throughout embryogenesis, from endothelial cell (EC) specification to vascular patterning into venous and arterial hierarchies. Following the initial assembly of ECs into a network of cord‐like structures, vascular expansion and remodeling occur rapidly through morphogenetic events including vessel sprouting, fusion, and pruning. In addition, vascular morphogenesis encompasses the process of lumen formation, critical for the transformation of cords into perfusable vascular tubes. Studies in mouse, zebrafish, frog, and human endothelial (...) cells have begun to outline the cellular and molecular requirements underlying lumen formation. Although the lumen can be generated through diverse mechanisms, the coordinated participation of multiple conserved molecules including transcription factors, small GTPases, and adhesion and polarity proteins remains a fundamental principle, leading us closer to a more thorough understanding of this complex event. (shrink)

The hardest part of replicating a genome is the beginning. The first step of DNA replication (called “initiation”) mobilizes a large number of specialized proteins (“initiators”) that recognize specific sequences or structural motifs in the DNA, unwind the double helix, protect the exposed ssDNA, and recruit the enzymatic activities required for DNA synthesis, such as helicases, primases and polymerases. All of these components are orderly assembled before the first nucleotide can be incorporated. On the occasion of the 50th anniversary of (...) the discovery of the DNA structure, we review our current knowledge of the molecular mechanisms that control initiation of DNA replication in eukaryotic cells, with particular emphasis on the recent identification of novel initiator proteins. We speculate how these initiators assemble molecular machines capable of performing specific biochemical tasks, such as loading a ring‐shaped helicase onto the DNA double helix. BioEssays 25:1158–1167, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

In eukaryotic cells a specialized organelle called the microtubule organizing center (MTOC) is responsible for disposition of microtubules in a radial, polarized array in interphase cells and in the spindle in mitotic cells. Eukaryotic cells across different species, and different cell types within single species, have morphologically diverse MTOCs, but these share a common function of organizing microtubule arrays. MTOCs effect microtubule organization by initiating microtubule assembly and anchoring microtubules by their slowly growing minus ends, thus ensuring that the rapidly (...) growing plus ends extend distally in each microtubule array. The goal is to define molecular components of the MTOC responsible for regulating microtubule assembly. One approach to defining the molecules responsible for MTOC function is to look for molecules common to all MTOCs. A newly discovered centrosomal protein, γ‐tubulin, is found in MTOCs in cells from many different organisms, and has several properties which make it a candidate for both initiation of microtubule assembly and anchorage. The hypothesis that γ‐tubulin plays a role in MTOCs in microtubule initiation and anchorage is currently being tested by a variety of experimental approaches. (shrink)

In a recent debate, Eric Drexler and Richard Smalley have discussed the chemical and physical possibility of constructing molecular assemblers - devices that guide chemical reactions by placing, with atomic precision, reactive molecules. Drexler insisted on the mechanical feasibility of such assemblers, whereas Smalley resisted the idea that such devices could be chemically constructed, because we do not have the required control. Underlying the debate, there are differences regarding the appropriate goals, methods, and theories of nanotechnology, and (...) the appropriate way of conceptualizing molecular assemblers. Not surprisingly, incommensurability emerges. In this paper, I assess the main features of the debate, the levels of the emerging incommensurability, and indicate one way in which the debate could be decided. (shrink)

To further comprehend how synthesis and assembly of myofibrillar components is regulated, several laboratories have undertaken genetic studies of muscle development in Drosophila melanogaster. This small fly lends itself well to classical and molecular genetic approaches, and possesses a set of muscle fibers, termed indirect flight muscles (IFM), which is particularly advantageous for such investigations. Structural and functional analyses of cloned Drosophila contractile protein genes have revealed that protein isoforms can be specified either by multigene families or by differentially (...) splicing primary transcripts of a single gene. Characterization of mutations which disrupt flight muscle development has so far revealed that profound abnormalities are caused by defective alleles of actin, tropomyosin, and myosin heavy‐chain genes. Muscle defects associated with particular alleles can be alleviated by integration of corresponding wild‐type gene copies into germ‐line chromosomes. Strategies for further applying genetic techniques to investigations of Drosophila muscle development are discussed. (shrink)

This is a brief historical view, based on my personal experience, of the phenomenological study of the assembly of actin in Japan. The morphogenesis and dynamics of protein filaments and cytoskeleton now represent one of the central problems in cell biology. The approach to this problem at the molecular level was first undertaken on actin from muscle.

It is now clear that two prominent nuclear domains, interchromatin granule clusters (IGCs) and Cajal bodies (CBs), contribute to the highly ordered organization of the extrachromosomal space of the cell nucleus. These functional domains represent structurally stable but highly dynamic nuclear organelles enriched in factors that are required for different nuclear activities, especially RNA biogenesis. IGCs are considered to be the main sites for storage, assembly, and/or recycling of the essential spliceosome components. CBs are involved in the biogenesis of several (...) classes of small RNPs as well as the modification of newly assembled small nuclear RNA. We have summarized data on the molecular composition, structure, and functional roles of IGCs and CBs in the nuclei of mammalian somatic cells and oocytes of some animals with a special focus on insects. We have focused on similarities and differences between the IGCs and CBs of oocytes and the well‐studied CBs and IGCs of cultured mammalian somatic cells. We have shown the heterogeneous character of oocyte IGCs and CBs, both in structure and molecular content. We have also demonstrated the unique capacity of oocytes to form close structural interactions between IGC and CB components. We proposed to consider these joint structures as integrated entities, sharing the features of both IGCs and CBs. (shrink)

Multisubunit protein complexes are essential for cellular function. Genetic analysis of essential processes requires special tools, among which temperature‐sensitive (Ts) mutants have historically been crucial. Many researchers assume that the effect of temperature on such mutants is to drive their proteolytic destruction. In fact, degradation‐mediated elimination of mutant proteins likely explains only a fraction of the phenotypes associated with Ts mutants. Here I discuss insights gained from analysis of Ts mutants in oligomeric proteins, with particular focus on the study of (...) septins, GTP‐binding subunits of cytoskeletal filaments whose structures and functions are the subject of current investigation in my and many other labs. I argue that the kinds of unbiased forward genetic approaches that generate Ts mutants provide information that is largely inaccessible to modern reverse genetic methodologies, and will continue to drive our understanding of higher‐order assembly by septins and other oligomeric proteins.Also watch the Video Abstract. (shrink)

Cell membranes are now emerging as finely tuned molecular systems, signifying that re‐evaluation of our understanding of their structure is essential. Although the idea that cell membrane lipid bilayers do little more than give shape and form to cells and limit diffusion between cells and their environment is totally passé, the structural, compositional, and functional complexity of lipid bilayers often catches cell and molecular biologists by surprise. Models of lipid bilayer structure have developed considerably since the heyday of (...) the fluid mosaic model, principally by the discovery of the restricted diffusion of membrane proteins and lipids within the plane of the bilayer. In reviewing this field, we now suggest that further refinement of current models is necessary and propose that describing lipid bilayers as “finely‐tuned molecular assemblies” best portrays their complexity and function. Also see the video abstract here: https://www.youtube.com/watch?v=ddkP-QRZTl8. (shrink)

The Nanoessence project aims to examine life at a sub-cellular level, re-examining space and scale within the human context. A single HaCat skin cell is analysed with an Atomic Force Microscope (AFM) to explore comparisons between, life and death at a nano level. The humanistic discourse concerning life is now being challenged by nanotechnological research that brings into question the concepts of what constitutes living. The Nanoessence project research is based on data gathered as part of a residency at SymbioticA, (...) Centre of Excellence in Biological Arts, University of Western Australia and the Nanochemistry Research Institute, (NRI) Curtin University of Technology. The space of the body can be seen at an atomic level as having no defining boundaries. More generally, molecular self-assembly seeks to use concepts of supramolecular chemistry, and molecular recognition in particular, to cause single-molecule components to automatically arrange themselves into some useful conformation (reference Wikipedia). Nano assembly, or bottom-up approach, is the construction of a supramolecular chemistry by the assembly of nanoscopic particles, or even atoms and molecules. The proposal for nanotechnology to reshape nature atom by atom develops an interesting debate as to the constitution of life. The Nanoessence project aims to construct a physical experience to examine this scientific and metaphysical world. Nanoessence is an interactive audio-visual installation. In the Nanoessence installation the viewer will interface with the visual and sonic presentation through his or her own breath. In the context of the project breath has a strong conceptual and metaphorical link to a Biblical inception of life. The project attempts to maintain a high quality of authentic data to engage the viewer in a sensorial qualitative experience of quantitative data. (shrink)

The human blood coagulation system comprises a series of linked glycoproteins that upon activation induce the generation of downstream enzymes ultimately forming fibrin. This process is primarily important to arrest bleeding (hemostasis). Hemostasis is a typical example of a molecular machine, where the assembly of substrates, enzymes, protein cofactors and calcium ions on a phospholipid surface markedly accelerates the rate of coagulation. Excess, pathological, coagulation activity occurs in “thrombosis”, the formation of an intravascular clot, which in the most dramatic (...) form precipitates in the microvasculature as disseminated intravascular coagulation. Thrombosis occurs according to a biochemical machine model in the case of atherothrombosis on a ruptured atherosclerotic plaque, but may develop at a slower rate in venous thrombosis, illustrating that the coagulation machinery can act at different velocities. The separate coagulation enzymes are also important in other biological processes, including inflammation for which the rapid conversion of one coagulation factor by the other is not a prerequisite. The latter role of coagulation enzymes may be related to the old and probably maintained function of the coagulation machine in innate immunity. BioEssays 25:1220–1228, 2003. © 2003 Wiley Perioicals, Inc. (shrink)

Dynamin is a GTPase that regulates late events in clathrin‐coated vesicle formation. Our current working model suggests that dynamin is targeted to coated pits in its unoccupied or GDP‐bound form, where it is initially distributed uniformly throughout the clathrin lattice. GTP/GDP exchange triggers its release from these sites and its assembly into short helices that encircle the necks of invaginated coated pits like a collar. GTP hydrolysis, which is required for vesicle detachment, presumably induces a concerted conformation change, tightening the (...) collar. Unlike most of its GTPase cousins that serve as molecular switches, dynamin has a low affinity for GTP, a very high intrinsic rate of GTP hydrolysis and functions as a homo‐oligomer. A concerted conformational change resulting from coordinated GTP hydrolysis by the dynamin oligomer might be sufficient to generate force. In this case, dynamin would be the first GTPase identified that acts as a structural protein with mechano‐chemical function. (shrink)

The eukaryotic genome is packaged into a periodic nucleoprotein structure termed chromatin. The repeating unit of chromatin, the nucleosome, consists of DNA that is wound nearly two times around an octamer of histone proteins. To facilitate DNA‐directed processes in chromatin, it is often necessary to rearrange or to mobilize the nucleosomes. This remodeling of the nucleosomes is achieved by the action of chromatin‐remodeling complexes, which are a family of ATP‐dependent molecular machines. Chromatin‐remodeling factors share a related ATPase subunit and (...) participate in transcriptional regulation, DNA repair, homologous recombination and chromatin assembly. In this review, we provide an overview of chromatin‐remodeling enzymes and discuss two possible mechanisms by which these factors might act to reorganize nucleosome structure. BioEssays 25:1192–1200, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Mitochondrial genomes represent relict bacterial genomes derived from a progenitor α‐proteobacterium that gave rise to all mitochondria through an ancient endosymbiosis. Evolution has massively reduced these genomes, yet despite relative simplicity their organization and expression has developed considerable novelty throughout eukaryotic evolution. Few organisms have reengineered their mitochondrial genomes as thoroughly as the protist lineage of dinoflagellates. Recent work reveals dinoflagellate mitochondrial genomes as likely the most gene‐impoverished of any free‐living eukaryote, encoding only two to three proteins. The organization and (...) expression of these genomes, however, is far from the simplicity their gene content would suggest. Gene duplication, fragmentation, and scrambling have resulted in an inflated and complex genome organization. Extensive RNA editing then recodes gene transcripts, and trans‐splicing is required to assemble full‐length transcripts for at least one fragmented gene. Even after these processes, messenger RNAs (mRNAs) lack canonical start codons and most transcripts have abandoned stop codons altogether. (shrink)

Although many active scientists deplore the publicity about Drexler's futuristic scenario, I will argue that the controversies it has generated are very useful, at least in one respect. They help clarify the metaphysical assumptions underlying nanotechnologies, which may prove very helpful for understanding their public and cultural impact. Both Drexler and his opponents take inspiration from living systems, which they both describe as machines. However there is a striking contrast in their respective views of molecular machineries. This paper based (...) on semipopular publications is an attempt to characterize the rival models of nanomachines and to disentangle the worldviews underpinning the uses of biological reference on both sides. Finally, in an effort to point out the historical roots of the contrast in the concepts of nanomachines, I raise the question of a divide between two cultures of nanotechnology. (shrink)

The relationship between kinetochores and nuclear pore complexes (NPCs) is intimate but poorly understood. Several NPC components and associated proteins are relocated to mitotic kinetochores to assist in different activities that ensure faithful chromosome segregation. Such is the case of the Mad1‐c‐Mad2 complex, the catalytic core of the spindle assembly checkpoint (SAC), a surveillance pathway that delays anaphase until all kinetochores are attached to spindle microtubules. Mad1‐c‐Mad2 is recruited to discrete domains of unattached kinetochores from where it promotes the rate‐limiting (...) step in the assembly of anaphase‐inhibitory complexes. SAC proficiency further requires Mad1‐c‐Mad2 to be anchored at NPCs during interphase. However, the mechanistic relevance of this arrangement for SAC function remains ill‐defined. Recent studies uncover the molecular underpinnings that coordinate the release of Mad1‐c‐Mad2 from NPCs with its prompt recruitment to kinetochores. Here, current knowledge on Mad1‐c‐Mad2 function and spatiotemporal regulation is reviewed and the critical questions that remain unanswered are highlighted. (shrink)

The molecular aspects of the microtubule system is a research area that has developed very rapidly during the past decade. Research on the assembly mechanisms and chemistry of tubulin and the molecular biology of microtubules have advanced our understanding of microtubule formation and its regulation. The emerging view of tubulin is of a macromolecule containing spatially discrete sequences that constitute functionally different domains with respect to self‐association, interactions with microtubule associated proteins (MAPs) and specific ligands. Recent studies point (...) to the role of the carboxyl‐terminal moiety of tubulin subunits in regulating its assembly into microtubules. These investigations combined with further studies on the spatial relationships between tubulin domains should provide new insights into the detailed structural basis of microtubule assembly. (shrink)

The central dogma of molecular biology dictates that, with only a few exceptions, information proceeds from DNA to protein through an RNA intermediate. Examining the enigmatic steps from prebiotic to biological chemistry, we take another road suggesting that primordial peptides acted as template for the self-assembly of the first nucleic acids polymers. Arguing in favour of a sort of archaic “reverse translation” from proteins to RNA, our basic premise is a Hadean Earth where key biomolecules such as amino acids, (...) polypeptides, purines, pyrimidines, nucleosides and nucleotides were available under different prebiotically plausible conditions, including meteorites delivery, shallow ponds and hydrothermal vents scenarios. Supporting a protein-first scenario alternative to the RNA world hypothesis, we propose the primeval occurrence of short two-dimensional peptides termed “selective amino acid- and nucleotide-matching oligopeptides” (henceforward SANMAOs) that noncovalently bind at the same time the polymerized amino acids and the single nucleotides dispersed in the prebiotic milieu. In this theoretical paper, we describe the chemical features of this hypothetical oligopeptide, its biological plausibility and its virtues from an evolutionary perspective. We provide a theoretical example of SANMAO’s selective pairing between amino acids and nucleosides, simulating a poly-Glycine peptide that acts as a template to build a purinic chain corresponding to the glycine’s extant triplet codon GGG. Further, we discuss how SANMAO might have endorsed the formation of low-fidelity RNA’s polymerized strains, well before the appearance of the accurate genetic material’s transmission ensured by the current translation apparatus. (shrink)

A simple molecular system is described consisting of the reciprocal linkage between an autocatalytic cycle and a self-assembling encapsulation process where the molecular constituents for the capsule are products of the autocatalysis. In a molecular environment sufficiently rich in the substrates, capsule growth will also occur with high predictability. Growth to closure will be most probable in the vicinity of the most prolific autocatalysis and will thus tend to spontaneously enclose supportive catalysts within the capsule interior. If (...) subsequently disrupted in the presence of new substrates, the released components will initiate production of additional catalytic and capsule components that will spontaneously re-assemble into one or more autocell replicas, thereby reconstituting and sometimes reproducing the original. In a diverse molecular environment, cycles of disruption and enclosure will cause auto-cells to incidentally encapsulate other molecules as well as reactive substrates. To the extent that any captured molecule can be incorporated into the autocatalytic process by virtue of structural degeneracy of the catalytic binding sites, the altered autocell will incorporate the new type of component into subsequent replications. Such altered autocells will be progenitors of “lineages” with variant characteristics that will differentially propagate with respect to the availability of commonly required substrates. Autocells are susceptible to a limited form of evolution, capable of leading to more efficient, more environmentally fitted, and more complex forms. This provides a simple demonstration of the plausibility of open-ended reproduction and evolvability without self-replicating template molecules or maintenance of persistent nonequilibrium chemistry. This model identifies an intermediate domain between prebiotic and biotic systems and bridges the gap from nonequilibrium thermodynamics to life. (shrink)

Our aim in this article is to attempt to discuss propagating organization of process, a poorly articulated union of matter, energy, work, constraints and that vexed concept, “information”, which unite in far from equilibrium living physical systems. Our hope is to stimulate discussions by philosophers of biology and biologists to further clarify the concepts we discuss here. We place our discussion in the broad context of a “general biology”, properties that might well be found in life anywhere in the cosmos, (...) freed from the specific examples of terrestrial life after 3.8 billion years of evolution. By placing the discussion in this wider, if still hypothetical, context, we also try to place in context some of the extant discussion of information as intimately related to DNA, RNA and protein transcription and translation processes. While characteristic of current terrestrial life, there are no compelling grounds to suppose the same mechanisms would be involved in any life form able to evolve by heritable variation and natural selection. In turn, this allows us to discuss at least briefly, the focus of much of the philosophy of biology on population genetics, which, of course, assumes DNA, RNA, proteins, and other features of terrestrial life. Presumably, evolution by natural selection—and perhaps self-organization—could occur on many worlds via different causal mechanisms. Here we seek a non-reductionist explanation for the synthesis, accumulation, and propagation of information, work, and constraint, which we hope will provide some insight into both the biotic and abiotic universe, in terms of both molecular self reproduction and the basic work energy cycle where work is the constrained release of energy into a few degrees of freedom. The typical requirement for work itself is to construct those very constraints on the release of energy that then constitute further work. Information creation, we argue, arises in two ways: first information as natural selection assembling the very constraints on the release of energy that then constitutes work and the propagation of organization. Second, information in a more extended sense is “semiotic”, that is about the world or internal state of the organism and requires appropriate response. The idea is to combine ideas from biology, physics, and computer science, to formulate explanatory hypotheses on how information can be captured and rendered in the expected physical manifestation, which can then participate in the propagation of the organization of process in the expected biological work cycles to create the diversity in our observable biosphere. Our conclusions, to date, of this enquiry suggest a foundation which views information as the construction of constraints, which, in their physical manifestation, partially underlie the processes of evolution to dynamically determine the fitness of organisms within the context of a biotic universe. (shrink)

The biogeographic contributions of Léon Croizat (1894–1982) and the conflictive relationships with his intellectual descendants and critics are analysed. Croizat’s panbiogeography assumed that vicariance is the most important biogeographic process and that dispersal does not contribute to biogeographic patterns. Dispersalist biogeographers criticized or avoided mentioning panbiogeography, especially in the context of the “hardening” of the Modern Synthesis. Researchers at the American Museum of Natural History associated panbiogeography with Hennig’s phylogenetic systematics, creating cladistic biogeography. On the other hand, a group of (...) New Zealand biologists formalized Croizat’s original concepts and soon began arguing with cladistic biogeographers over the relative merits of their approaches. In Latin America, panbiogeography and cladistic biogeography were incorporated as parts of an integrative approach. A recent development, molecular panbiogeography, is based on the use of molecular phylogenetic data. The current practice shows that some authors insist on considering panbiogeography as the only appropriate approach and vicariance as the only relevant process, whereas others accept Croizat’s dictum “Earth and life evolve together” as a useful guide to understanding broad, general patterns, but recognize that dispersal also contributes substantially to biotic assembly. The framework of integrative pluralism allows to explain the complexities of the biogeographic processes involved in biotic assembly without the need of unification on a large scale. This historical analysis intersects with the existing historiography of the Modern Synthesis and may provide some insights on the dynamics of integrative pluralism, which may be especially relevant in the current development of the Extended Synthesis. (shrink)

The majority of G protein-coupled receptors (GPCRs) self-assemble in the form dimeric/oligomeric complexes along the plasma membrane. Due to the molecular interactions they participate, GPCRs can potentially provide the framework for discriminating a wide variety of intercellular signals, as based on some kind of combinatorial receptor codes. GPCRs can in fact transduce signals from the external milieu by modifying the activity of such intracellular proteins as adenylyl cyclases, phospholipases and ion channels via interactions with specific G-proteins. However, in spite (...) of the number of cell functions they can actually control, both GPCRs and their associated signal transduction pathways are extremely well conserved, for only a few alleles with null or minor functional alterations have so far been found. This would seem to suggest that, beside a mechanism for DNA repairing, there must be another level of quality control that may help maintaining GPCRs rather stable throughout evolution. We propose here receptor oligomerization to be a basic molecular mechanism controlling GPCRs redundancy in many different cell types, and the plasma membrane as the first hierarchical cell structure at which selective categorical sensing may occur. Categorical sensing can be seen as the cellular capacity for identifying and ordering complex patterns of mixed signals out of a contextual matrix, i.e., the recognition of meaningful patterns out of ubiquitous signals. In this context, redundancy and degeneracy may appear as the required feature to integrate the cell system into functional units of progressively higher hierarchical levels. (shrink)

Many believe that nanotechnology will be disruptive to our society. Presumably, this means that some people and even whole industries will be undermined by technological developments that nanoscience makes possible. This, in turn, implies that we should anticipate potential workforce disruptions, mitigate in advance social problems likely to arise, and work to fairly distribute the future benefits of nanotechnology. This general, somewhat vague sense of disruption, is very difficult to specify – what will it entail? And how can we responsibly (...) anticipate and mitigate any problems? We can't even clearly state what the problems are anticipated to be. In fact, when we move from sweeping policy statements to more concrete accounts, nanotechnology seems to bifurcate into two divergent streams: one is fairly continuous with current developments, extending extant science in a quantitative way; the other is radically new, and includes science fiction-like dreams of molecular manufacturing and assemblers, with their utopian scenarios of absolute plenty. In these cases, “disruption” takes on the valence of Huxley's brave new world. (shrink)

Several features of the yeast mitochondrial genome, including high mutation rate, dynamic genomic structure, small effective population size, and dispensability for cellular viability, make it a promising candidate for generating hybrid incompatibility and driving speciation. Cytonuclear incompatibility, a specific type of Dobzhansky‐Muller genetic incompatibility caused by improper interactions between mitochondrial and nuclear genomes, has previously been observed in a variety of organisms, yet its role in speciation remains obscure. Recent studies in Saccharomyces yeast species provide a new insight, with experimental (...) evidence that cytonuclear incompatibility and DNA sequence divergence are both causes of the reproductive isolation of different yeast species. Interestingly, these two mechanisms seem to be perfectly complementary to each other in terms of their effects and evolutionary trajectories. Direct molecular analyses of the incompatible genes in yeasts have started to shed light on the evolutionary forces driving speciation. Editor's suggested further reading in BioEssaysThe cytoplasmic structure hypothesis for ribosome assembly, vertical inheritance, and phylogeny AbstractMitochondrial bioenergetics as a major motive force of speciation Abstract. (shrink)

Systems Biology and the Modern Synthesis are recent versions of two classical biological paradigms that are known as structuralism and functionalism, or internalism and externalism. According to functionalism (or externalism), living matter is a fundamentally passive entity that owes its organization to external forces (functions that shape organs) or to an external organizing agent (natural selection). Structuralism (or internalism), is the view that living matter is an intrinsically active entity that is capable of organizing itself from within, with purely internal (...) processes that are based on mathematical principles and physical laws. At the molecular level, the basic mechanism of the Modern Synthesis is molecular copying, the process that leads in the short run to heredity and in the long run to natural selection. The basic mechanism of Systems Biology, instead, is self-assembly, the process by which many supramolecular structures are formed by the spontaneous aggregation of their components. In addition to molecular copying and self-assembly, however, molecular biology has uncovered also a third great mechanism at the heart of life. The existence of the genetic code and of many other organic codes in Nature tells us that molecular coding is a biological reality and we need therefore a framework that accounts for it. This framework is Code biology, the study of the codes of life, a new field of research that brings to light an entirely new dimension of the living world and gives us a completely new understanding of the origin and the evolution of life. (shrink)

A cell's biochemistry is now known to be the biochemistry of molecular machines, that is, protein complexes that are assembled and dismantled in particular locations within the cell as needed. One important element in our understanding has been the ability to begin to see where proteins are in cells and what they are doing as they go about their business. Accordingly, there is now a strong impetus to discover new ways of looking at the workings of proteins in living (...) cells. Although the use of fluorescent tags to track individual proteins in cells has a long history, the availability of laser-based confocal microscopes and the imaginative exploitation of the green fluorescent protein from jellyfish have provided new tools of great diversity and utility. It is now possible to watch a protein bind its substrate or its partners in real time and with submicron resolution within a single cell. The importance of processes of self-organisation represented by protein folding on the one hand and subcellular organelles on the other are well recognised. Self-organisation at the intermediate level of multimeric protein complexes is now open to inspection. BioEssays 22:180–187, 2000. ©2000 John Wiley & Sons, Inc. (shrink)

Motile bacteria respond to environmental cues to move to more favorable locations. The components of the chemotaxis signal transduction systems that mediate these responses are highly conserved among prokaryotes including both eubacterial and archael species. The best‐studied system is that found in Escherichia coli. Attractant and repellant chemicals are sensed through their interactions with transmembrane chemoreceptor proteins that are localized in multimeric assemblies at one or both cell poles together with a histidine protein kinase, CheA, an SH3‐like adaptor protein, CheW, (...) and a phosphoprotein phosphatase, CheZ. These multimeric protein assemblies act to control the level of phosphorylation of a response regulator, CheY, which dictates flagellar motion. Bacterial chemotaxis is one of the most‐understood signal transduction systems, and many biochemical and structural details of this system have been elucidated. This is an exciting field of study because the depth of knowledge now allows the detailed molecular mechanisms of transmembrane signaling and signal processing to be investigated. BioEssays 28:9–22, 2006. © 2005 Wiley Periodicals, Inc. (shrink)

The concept of a “chemical speciation”, as defined by in the year 2000, is grounded in an empiricist semantics. It is a static concept, as it is associated with the ontological category of the chemical state of the distribution of chemical species in a system and is further restricted to chemical species of a single element as it excludes chemical species with more complex chemical systemic subunits, such as molecular species, crystals, or nanoparticles. In this work, we propose a (...) new definition of “chemical speciation” based on a semantics of meaning, applying Mario Bunge’s philosophical system. Chemical speciation is the distribution of chemical systemic subunits amongst defined chemical species in a system. Additionally, we propose two dynamic concepts associated with chemical speciation: chemical species transformation and chemical species evolution. These concepts aim to account for the chemical changes that explain both the diversity of chemical species sharing common systemic subunits and the historical emergence of new modes of chemical speciation. These modes, in turn, explain the appearance of new systemic chemical subunits and novel substantial properties. Our definitions have the advantage of being consistent with general theories of the evolution of matter, such Assembly Theory. Additionally, at the chemical level, this approach encompasses broader systemic chemical subunits beyond elemental particles, allowing for the chemical speciation of families of molecules, crystals, nanoparticles, etc. Finally, our proposal offers the advantage of overcoming the issue of arbitrariness in choosing the reference systemic chemical subunit by linking this choice to the concepts of substantial property, and function. (shrink)

Videogames are a unique artistic form, and to analyse and understand them an equally unique language is required. Cremin turns to Deleuze and Guattari's non-representational philosophy to develop a conceptual toolkit for thinking anew about videogames and our relationship to them. Rather than approach videogames through a language suited to other media forms, Cremin invites us to think in terms of a videogame plane and the compositions of developers and players who bring them to life. According to Cremin, we are (...) not simply playing videogames, we are creating them. We exceed our own bodily limitations by assembling forces with the elements they are made up of. The book develops a critical methodology that can explain what every videogame, irrespective of genre or technology, has in common and proceeds on this basis to analyse their differences. Drawing from a wide range of examples spanning the history of the medium, Cremin discerns the qualities inherent to those regarded as classics and what those qualities enable the player to do. Exploring Videogames with Deleuze and Guattari analyses different aspects of the medium, including the social and cultural context in which videogames are played, to develop a nuanced perspective on gendered narratives, caricatures and glorifications of war. It considers the processes and relationships that have given rise to industrial giants, the spiralling costs of making videogames and the pressure this places developers under to produce standard variations of winning formulas. The book invites the reader to embark on a molecular journey through worlds neither 'virtual' nor 'real' exceeding image, analogy and metaphor. With clear explanations and detailed analysis, Cremin demonstrates the value of a Deleuzian approach to the study of videogames, making it an accessible and valuable resource for students, scholars, developers and enthusiasts. (shrink)

The retinal pigment epithelium (RPE) is a specialized epithelium at the back of the eye that carries out a variety of functions essential for visual health. Recent studies have advanced our molecular understanding of one of the major functions of the RPE; phagocytosis of spent photoreceptor outer segments (POS). Notably, a mechanical link, formed between apical integrins bound to extracellular POS and the intracellular actomyosin cytoskeleton, is proposed to drive the internalization of POS. The process may involve a “nibbling” (...) action, as an initial step, to sever outer segment tips. These insights have led us to hypothesize an “integrin adhesome‐like” network, atypically assembled at apical membrane RPE‐POS contacts. I propose that this hypothetical network orchestrates the complex membrane remodeling events required for particle internalization. Therefore, its analysis and characterization will likely lead to a more comprehensive understanding of the molecular mechanisms that control POS phagocytosis. (shrink)

Vacuolar ATPases (V‐ATPases, V1Vo‐ATPases) are rotary motor proton pumps that acidify intracellular compartments, and, when localized to the plasma membrane, the extracellular space. V‐ATPase is regulated by a unique process referred to as reversible disassembly, wherein V1‐ATPase disengages from Vo proton channel in response to diverse environmental signals. Whereas the disassembly step of this process is ATP dependent, the (re)assembly step is not, but requires the action of a heterotrimeric chaperone referred to as the RAVE complex. Recently, an alternative pathway (...) of holoenzyme disassembly was discovered that involves binding of Oxidation Resistance 1 (Oxr1p), a poorly characterized protein implicated in oxidative stress response. Unlike conventional reversible disassembly, which depends on enzyme activity, Oxr1p induced dissociation can occur in absence of ATP. Yeast Oxr1p belongs to the family of TLDc domain containing proteins that are conserved from yeast to mammals, and have been implicated in V‐ATPase function in a variety of tissues. This brief perspective summarizes what we know about the molecular mechanisms governing both reversible (ATP dependent) and Oxr1p driven (ATP independent) V‐ATPase dissociation into autoinhibited V1 and Vo subcomplexes. (shrink)

This volume is the latest in a series of books and articles stretching back more than three decades on a theme quite startling in its claims and implications: that terrestrial life did not originate on Earth but arrived in the form of cells or bacteria from outer space. The idea of “panspermia,” that the seeds of life are spread from planet to planet, dates to the 19th century with the ideas of Lord Kelvin. It was championed by the Swedish physicist, (...) chemist, and Nobelist Svante Arrhenius at the beginning of the 20th century. Once scientists recognized the difficulties of life surviving in the conditions of interplanetary and interstellar space, by the 1960s a neo-panspermia became popular: not life itself, but prebiotic chemicals were the new seeds of life, made more likely by the discovery of numerous complex organic molecules in meteorites, comets, and interstellar molecular clouds. But the difficulties of synthesizing anything more complicated than amino acids in the wake of the famous Miller-Urey experiment in 1953 kept alive the idea that life itself may be spread throughout the universe. At the center of this work is Chandra Wickramasinghe, a research student of the maverick astronomer Fred Hoyle. In 1962 Hoyle became interested in the origin and nature of interstellar dust, in particular as found in dense molecular clouds, and he and Wickramasinghe set to work on the problem. They became convinced that dust could not form inside molecular clouds, but must have originated in the atmospheres of cool stars, protoplanetary discs, or supernova ejecta, a theory now widely accepted. It was the next steps that became increasingly controversial: that the spectroscopic signature of dust was best explained by complex biomolecules such as cellulose; that biomolecules were assembled into still more complex forms inside comets; and that the living cells and bacteria generated there were responsible for the origin of life on Earth. And not only that: Hoyle and Wickramasinghe argued that the delivery of bacteria from space continues, affecting both the origin and the ongoing evolution of life, and may even be responsible for certain diseases on Earth. These theories were not only reported in reputable scientific journals such as Nature, but also in popular books including Lifecloud (1978), Diseases from Space (1979), and Evolution from Space (1981). Biologists were not impressed; Lynn Margulis, not known for the timidity of her own theories such as endosymbiosis, called the first book “wanton, amusing, promiscuous fiction.”. (shrink)

The origin of the notochord is one of the key remaining mysteries of our evolutionary ancestry. Here, we present a multi‐level comparison of the chordate notochord to the axochord, a paired axial muscle spanning the ventral midline of annelid worms and other invertebrates. At the cellular level, comparative molecular profiling in the marine annelids P. dumerilii and C. teleta reveals expression of similar, specific gene sets in presumptive axochordal and notochordal cells. These cells also occupy corresponding positions in a (...) conserved anatomical topology and undergo similar morphogenetic movements. At the organ level, a detailed comparison of bilaterian musculatures reveals that most phyla form axochord‐like muscles, suggesting that such a muscle was already present in urbilaterian ancestors. Integrating comparative evidence at the cell and organ level, we propose that the notochord evolved by modification of a ventromedian muscle followed by the assembly of an axial complex supporting swimming in vertebrate ancestors. (shrink)