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Cell structure and dynamics
Available online at www.sciencedirect.com
Cell structure and dynamics Editorial overview Arshad Desai and Marileen Dogterom Current Opinion in Cell Biology 2010, 22:1–3 Available online 25th January 2010 0955-0674/$ – see front matter # 2010 Elsevier Ltd. All rights reserved. DOI 10.1016/j.ceb.2010.01.003
Arshad Desai Department of Cellular & Molecular Medicine, Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093-0653, United States e-mail: [email protected]
Arshad Desai is at the Ludwig Institute for Cancer Research/ University of California, San Diego. He has a long-standing interest in the microtubule cytoskeleton and its regulation. His current research focus is on the mechanisms that direct accurate chromosome segregation during cell division.
Marileen Dogterom FOM Institute for Atomic and Molecular Physics (AMOLF), Science Park 104, 1098 XG Amsterdam, The Netherlands e-mail: [email protected]
Marileen Dogterom was trained as a physicist. Her lab focuses on quantitative in vitro and in vivo studies of the dynamics and organization of the microtubule cytoskeleton, with an emphasis on microtubule force generation. She currently heads the Biomolecular Physics Department of the FOM Institute AMOLF in Amsterdam, and holds an affiliated professorship at the Physics Department of the University of Leiden.
www.sciencedirect.com
IT TAKES TWO (to highlight the interdisciplinary nature of modern cell biology) In recent years, we have witnessed an explosion of information in cell biology. The discovery and characterization of molecular machines participating in numerous cellular processes, which has historically dominated experimental efforts, is nearing an end: there is an emerging consensus that with modern genomic, proteomic and informatic approaches the majority of relevant players are at hand. The advent of high-resolution imaging and biophysical methods coupled with the development of an impressive palette of probes is driving increasingly sophisticated in vivo and in vitro studies of cellular molecular machines. All of these rapid developments are posing new challenges and have revealed a necessity for interdisciplinary experimental as well as theoretical approaches in the analysis of cellular mechanisms. The contents of this issue reflect this need in the collaborative effort of a cell biologist and a biological physicist to summarize new advances in areas traditionally covered by the Cell Structure and Dynamics issue, highlighting the increasing importance of theory and the influence of physics in the study of cellular mechanisms. The issue begins with a pair of papers, the first by Holzbaur and Goldman that masterfully summarizes recent advances in studies of intracellular motility, where coordinated action of molecular motors is involved in transport of various cargos. In the companion paper, Gue´rin, Joanny, and colleagues describe theoretical efforts directed toward describing the coordinated action of molecular motors, highlighting the point that in biology, as in physics, ‘more is different’. These reviews provide a glimpse into how studies of molecular motor-mediated transport are progressing from precisely controlled in vitro analysis of single enzymes to a more realistic cellular environment. Tolic´-Nørrylykke continues the theme of in vivo biophysics, describing elegant work in fission yeast that has provided important insights into the interplay between dynamics, length regulation, and force generation for the microtubule cytoskeleton. Her review highlights how precise perturbations using optical methods can be used to distinguish between specific mechanisms in vivo and thereby reveal general principles operating in diverse biological contexts. MacKintosh and Schmidt next provide an illuminating and educational overview of the emerging field of ‘active cellular materials’ — they describe how physics is providing insight into the reasons as to why biological materials, such as cytoskeletal polymer-motor networks, are special. The exciting developments in this area are extending to a Current Opinion in Cell Biology 2010, 22:1–3
2 Cell structure and dynamics
rigorous level the intuitive sense that cell biologists have about the properties of cellular macromolecular assemblies. They are also revealing features that will be of great interest to physicists. The emphasis on approaching cellular processes from a combined theoretical and experimental angle continues in the discussion of endocytosis by Liu, Drubin, and colleagues. They focus on a model in which mechanochemical feedback between membrane curvature and biochemical reactions drives the endocytic reaction. Their discussion nicely highlights how detailed experimental analysis of specific components is now transitioning to integrative approaches where theory is being used to develop models and guide future work. Discussion of the mechanism by which complicated macromolecular assemblies participate in cellular processes continues in the next review by Goshima and Kimura, who summarize the emerging view that microtubule-dependent microtubule formation is critical for spindle assembly. They describe the functional genomics efforts that identified the conserved protein complex implicated in this process and summarize advances from high-resolution imaging and mathematical modeling that are altering traditional views of spindle assembly and structure. Cellular macromolecular machines are further highlighted in the next two reviews, on cytokinesis by Pollard, and on chromosome segregation by Joglekar and colleagues. Pollard lucidly summarizes current work on the formation and function of the contractile ring, the actin–myosin assembly whose constriction cleaves the mother cell between the segregated chromosomes. His comparison of contractile rings in fungi and metazoans highlights both conserved and apparently distinct mechanisms. Such comparisons across divergent organisms are becoming increasingly important not only to help classify specific components and mechanisms but also to place detailed studies in one species into a broader biological context. Joglekar, Bloom, and Salmon similarly discuss the kinetochore, the macromolecular machine built on the centromere region of chromosomes to connect to spindle microtubules. The authors present prevalent models for force generation at the kinetochore–microtubule interface, summarize key players involved at this interface, and discuss new insights gleaned into the force generation mechanism from the definition of the molecular architecture of fungal and vertebrate kinetochores revealed by innovative microscopic approaches. All three of these reviews nicely highlight advances and challenges in how modern cell biology is tackling complicated macromolecular assemblies comprised of 50–100 proteins. They also summarize the increasing importance of theoretical modeling in the study of such machines. The comparison of fungal and metazoan/vertebrate contractile rings and kinetochores in the Pollard and Joglekar reviews both rely on primary sequence conservation as a means of assessing homology across evolutionary disCurrent Opinion in Cell Biology 2010, 22:1–3
tance. In his review, Egelman presents evidence that primary sequence conservation can still be accompanied by significant divergence in quaternary structure of protein assemblies. Such quaternary structure divergence is a critical evolutionary mechanism, and underlies the ability of related structures to perform distinct functions. Egelman discusses the concept of divergence of quaternary structure primarily in the context of bacterial flagella and Type III secretion systems, related assemblies with distinct functions in bacteria. He goes on to comment how insights derived from the analysis of divergence of quaternary structure debunk the concept of ‘irreducible complexity’ that has been applied by proponents of ‘intelligent design’ to intricate macromolecular biological assemblies, such as flagella. Baldari and Rosenbaum next provide an insightful and persuasive argument for a new function for cilia, the microtubule-based cellular projections whose sensory and motile roles have been extensively studied. The authors review recent evidence that the intra-flagellar transport machinery, discovered based on its role in building and maintaining cilia and assumed to exclusively function in cilia, has functions outside of the context of cilia, notably in processes involving exocytosis. The authors suggest that the cilium, in addition to its motile and sensory functions, is a specialized membrane compartment with a secretory function. This proposal may prove important for elucidating the link between cilia and developmental signaling mechanisms that has been linked to a wide spectrum of human diseases. Continuing the theme of unexpected and significant new developments, Klar and colleagues summarize evidence that the two sister chromatids that are the cargo for segregation on the spindle are not always equivalent. They describe evidence for selective mitotic chromatid segregation, which they propose is critical for asymmetric cell division during the development of multicellular organisms. Their proposal is supported by very recent work, where direct visualization of marked chromatids has revealed asymmetries in their segregation [1]. A trio of reviews next discusses new advances in our understanding of the regulation of the microtubule cytoskeleton. Slep provides an expert summary of structural and mechanistic analysis of microtubule-end binding proteins. His review details in an insightful manner what has been learned from extensive structural and biophysical studies of these fascinating proteins. Roll-Mecak and McNally review microtubule-severing enzymes, which are widely conserved AAA ATPases, whose mechanism of action is starting to be elucidated, just as their wide biological significance is coming to light. Finally Etienne-Manneville reviews posttranslational regulation of microtubule dynamics, focusing both on regulators, their control by signaling pathways, and exciting recent advances in understanding the mechanisms and biological functions of tubulin posttranslational modifications. www.sciencedirect.com
Editorial overview Desai and Dogterom 3
Last but not least, Meignin and Davis provide a scholarly review of advances in elucidating the mechanisms controlling intracellular mRNA localization. While selected examples of mRNA localization have been the subject of intensive study for quite some time, recent genomic efforts have established surprisingly widespread occurrence of asymmetric mRNA localization. Davis et al. review classically studied mechanisms as well as new physics-inspired mechanisms that have emerged as potential means for altering message localization in vivo.
cell biology research. The success of an interdisciplinary, combined theoretical and experimental approach will however always rely on the availability of sufficient (quantitative) information about the system and an ability to reduce the description of cellular mechanisms to their essential parts. It will be a challenge for the future to expand this approach to the majority of cellular complexes and pathways that consist of more than just a few components.
References 1.
Summing up, this issue provides a glimpse into the mix of approaches that is increasingly becoming the standard in
www.sciencedirect.com
Falconer E, Chavez EA, Henderson A, Poon SSS, McKinney S, Brown L, Huntsman DG, Lansdorp PM: Identification of sister chromatids by DNA template strand sequences. Nature 2010, 463:93-97.
Current Opinion in Cell Biology 2010, 22:1–3
Cell structure and dynamics Editorial overview Arshad Desai and Marileen Dogterom Current Opinion in Cell Biology 2010, 22:1–3 Available online 25th January 2010 0955-0674/$ – see front matter # 2010 Elsevier Ltd. All rights reserved. DOI 10.1016/j.ceb.2010.01.003
Arshad Desai Department of Cellular & Molecular Medicine, Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093-0653, United States e-mail: [email protected]
Arshad Desai is at the Ludwig Institute for Cancer Research/ University of California, San Diego. He has a long-standing interest in the microtubule cytoskeleton and its regulation. His current research focus is on the mechanisms that direct accurate chromosome segregation during cell division.
Marileen Dogterom FOM Institute for Atomic and Molecular Physics (AMOLF), Science Park 104, 1098 XG Amsterdam, The Netherlands e-mail: [email protected]
Marileen Dogterom was trained as a physicist. Her lab focuses on quantitative in vitro and in vivo studies of the dynamics and organization of the microtubule cytoskeleton, with an emphasis on microtubule force generation. She currently heads the Biomolecular Physics Department of the FOM Institute AMOLF in Amsterdam, and holds an affiliated professorship at the Physics Department of the University of Leiden.
www.sciencedirect.com
IT TAKES TWO (to highlight the interdisciplinary nature of modern cell biology) In recent years, we have witnessed an explosion of information in cell biology. The discovery and characterization of molecular machines participating in numerous cellular processes, which has historically dominated experimental efforts, is nearing an end: there is an emerging consensus that with modern genomic, proteomic and informatic approaches the majority of relevant players are at hand. The advent of high-resolution imaging and biophysical methods coupled with the development of an impressive palette of probes is driving increasingly sophisticated in vivo and in vitro studies of cellular molecular machines. All of these rapid developments are posing new challenges and have revealed a necessity for interdisciplinary experimental as well as theoretical approaches in the analysis of cellular mechanisms. The contents of this issue reflect this need in the collaborative effort of a cell biologist and a biological physicist to summarize new advances in areas traditionally covered by the Cell Structure and Dynamics issue, highlighting the increasing importance of theory and the influence of physics in the study of cellular mechanisms. The issue begins with a pair of papers, the first by Holzbaur and Goldman that masterfully summarizes recent advances in studies of intracellular motility, where coordinated action of molecular motors is involved in transport of various cargos. In the companion paper, Gue´rin, Joanny, and colleagues describe theoretical efforts directed toward describing the coordinated action of molecular motors, highlighting the point that in biology, as in physics, ‘more is different’. These reviews provide a glimpse into how studies of molecular motor-mediated transport are progressing from precisely controlled in vitro analysis of single enzymes to a more realistic cellular environment. Tolic´-Nørrylykke continues the theme of in vivo biophysics, describing elegant work in fission yeast that has provided important insights into the interplay between dynamics, length regulation, and force generation for the microtubule cytoskeleton. Her review highlights how precise perturbations using optical methods can be used to distinguish between specific mechanisms in vivo and thereby reveal general principles operating in diverse biological contexts. MacKintosh and Schmidt next provide an illuminating and educational overview of the emerging field of ‘active cellular materials’ — they describe how physics is providing insight into the reasons as to why biological materials, such as cytoskeletal polymer-motor networks, are special. The exciting developments in this area are extending to a Current Opinion in Cell Biology 2010, 22:1–3
2 Cell structure and dynamics
rigorous level the intuitive sense that cell biologists have about the properties of cellular macromolecular assemblies. They are also revealing features that will be of great interest to physicists. The emphasis on approaching cellular processes from a combined theoretical and experimental angle continues in the discussion of endocytosis by Liu, Drubin, and colleagues. They focus on a model in which mechanochemical feedback between membrane curvature and biochemical reactions drives the endocytic reaction. Their discussion nicely highlights how detailed experimental analysis of specific components is now transitioning to integrative approaches where theory is being used to develop models and guide future work. Discussion of the mechanism by which complicated macromolecular assemblies participate in cellular processes continues in the next review by Goshima and Kimura, who summarize the emerging view that microtubule-dependent microtubule formation is critical for spindle assembly. They describe the functional genomics efforts that identified the conserved protein complex implicated in this process and summarize advances from high-resolution imaging and mathematical modeling that are altering traditional views of spindle assembly and structure. Cellular macromolecular machines are further highlighted in the next two reviews, on cytokinesis by Pollard, and on chromosome segregation by Joglekar and colleagues. Pollard lucidly summarizes current work on the formation and function of the contractile ring, the actin–myosin assembly whose constriction cleaves the mother cell between the segregated chromosomes. His comparison of contractile rings in fungi and metazoans highlights both conserved and apparently distinct mechanisms. Such comparisons across divergent organisms are becoming increasingly important not only to help classify specific components and mechanisms but also to place detailed studies in one species into a broader biological context. Joglekar, Bloom, and Salmon similarly discuss the kinetochore, the macromolecular machine built on the centromere region of chromosomes to connect to spindle microtubules. The authors present prevalent models for force generation at the kinetochore–microtubule interface, summarize key players involved at this interface, and discuss new insights gleaned into the force generation mechanism from the definition of the molecular architecture of fungal and vertebrate kinetochores revealed by innovative microscopic approaches. All three of these reviews nicely highlight advances and challenges in how modern cell biology is tackling complicated macromolecular assemblies comprised of 50–100 proteins. They also summarize the increasing importance of theoretical modeling in the study of such machines. The comparison of fungal and metazoan/vertebrate contractile rings and kinetochores in the Pollard and Joglekar reviews both rely on primary sequence conservation as a means of assessing homology across evolutionary disCurrent Opinion in Cell Biology 2010, 22:1–3
tance. In his review, Egelman presents evidence that primary sequence conservation can still be accompanied by significant divergence in quaternary structure of protein assemblies. Such quaternary structure divergence is a critical evolutionary mechanism, and underlies the ability of related structures to perform distinct functions. Egelman discusses the concept of divergence of quaternary structure primarily in the context of bacterial flagella and Type III secretion systems, related assemblies with distinct functions in bacteria. He goes on to comment how insights derived from the analysis of divergence of quaternary structure debunk the concept of ‘irreducible complexity’ that has been applied by proponents of ‘intelligent design’ to intricate macromolecular biological assemblies, such as flagella. Baldari and Rosenbaum next provide an insightful and persuasive argument for a new function for cilia, the microtubule-based cellular projections whose sensory and motile roles have been extensively studied. The authors review recent evidence that the intra-flagellar transport machinery, discovered based on its role in building and maintaining cilia and assumed to exclusively function in cilia, has functions outside of the context of cilia, notably in processes involving exocytosis. The authors suggest that the cilium, in addition to its motile and sensory functions, is a specialized membrane compartment with a secretory function. This proposal may prove important for elucidating the link between cilia and developmental signaling mechanisms that has been linked to a wide spectrum of human diseases. Continuing the theme of unexpected and significant new developments, Klar and colleagues summarize evidence that the two sister chromatids that are the cargo for segregation on the spindle are not always equivalent. They describe evidence for selective mitotic chromatid segregation, which they propose is critical for asymmetric cell division during the development of multicellular organisms. Their proposal is supported by very recent work, where direct visualization of marked chromatids has revealed asymmetries in their segregation [1]. A trio of reviews next discusses new advances in our understanding of the regulation of the microtubule cytoskeleton. Slep provides an expert summary of structural and mechanistic analysis of microtubule-end binding proteins. His review details in an insightful manner what has been learned from extensive structural and biophysical studies of these fascinating proteins. Roll-Mecak and McNally review microtubule-severing enzymes, which are widely conserved AAA ATPases, whose mechanism of action is starting to be elucidated, just as their wide biological significance is coming to light. Finally Etienne-Manneville reviews posttranslational regulation of microtubule dynamics, focusing both on regulators, their control by signaling pathways, and exciting recent advances in understanding the mechanisms and biological functions of tubulin posttranslational modifications. www.sciencedirect.com
Editorial overview Desai and Dogterom 3
Last but not least, Meignin and Davis provide a scholarly review of advances in elucidating the mechanisms controlling intracellular mRNA localization. While selected examples of mRNA localization have been the subject of intensive study for quite some time, recent genomic efforts have established surprisingly widespread occurrence of asymmetric mRNA localization. Davis et al. review classically studied mechanisms as well as new physics-inspired mechanisms that have emerged as potential means for altering message localization in vivo.
cell biology research. The success of an interdisciplinary, combined theoretical and experimental approach will however always rely on the availability of sufficient (quantitative) information about the system and an ability to reduce the description of cellular mechanisms to their essential parts. It will be a challenge for the future to expand this approach to the majority of cellular complexes and pathways that consist of more than just a few components.
References 1.
Summing up, this issue provides a glimpse into the mix of approaches that is increasingly becoming the standard in
www.sciencedirect.com
Falconer E, Chavez EA, Henderson A, Poon SSS, McKinney S, Brown L, Huntsman DG, Lansdorp PM: Identification of sister chromatids by DNA template strand sequences. Nature 2010, 463:93-97.
Current Opinion in Cell Biology 2010, 22:1–3