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出版者:Springer

作者:Aktories, K.; Altschuler, D. L.; Anderson, M. W.

出品人:

页数:697

译者:

出版时间:1994-1-14

价格:USD 424.00

装帧:Hardcover

isbn号码:9783540567738

丛书系列:

图书标签:

GTPases
Signal Transduction
Cell Biology
Molecular Biology
Protein Biochemistry
Cell Signaling
Regulation
Cancer
Membrane Trafficking
Intracellular Transport

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GTPases in Biology: A Comprehensive Exploration This volume delves into the intricate world of GTPases, a superfamily of proteins that act as molecular switches, orchestrating a vast array of cellular processes fundamental to life. Far from being mere participants, GTPases are central regulators, their dynamic on and off states dictating the timing, direction, and execution of critical events within the cell. This book offers an in-depth examination of their structure, function, regulation, and diverse roles across a spectrum of biological contexts, providing a foundational understanding for researchers and students alike. The Molecular Machinery of GTPases: Structure and Mechanism At the heart of GTPase function lies their ability to bind and hydrolyze guanosine triphosphate (GTP) and guanosine diphosphate (GDP). This binding and hydrolysis cycle is the very engine that drives their activity, allowing them to cycle between an active, GTP-bound state and an inactive, GDP-bound state. The book meticulously dissects the molecular architecture of GTPases, highlighting the conserved domains responsible for nucleotide binding and hydrolysis. Particular attention is paid to the P-loop, a critical phosphate-binding loop, and the catalytic lysine residue that facilitates GTP hydrolysis. The subtle conformational changes that accompany nucleotide binding and hydrolysis are explored in detail, revealing how these shifts translate into functional interactions with downstream effector proteins. The mechanisms of GTPase activation and inactivation are central to their regulatory role. Guanine nucleotide exchange factors (GEFs) are introduced as potent activators, catalyzing the release of GDP and facilitating the binding of GTP. Their diverse structural motifs and mechanisms of interaction with different GTPase families are elucidated, showcasing the specificity and complexity of this regulatory step. Conversely, GTPase-activating proteins (GAPs) are presented as crucial negative regulators, accelerating the intrinsic GTP hydrolysis rate and thus promoting inactivation. The book examines the distinct catalytic mechanisms employed by GAPs and their role in fine-tuning GTPase signaling duration. Furthermore, the influence of guanine nucleotide dissociation inhibitors (GDIs) on GDP-bound GTPases is explored, revealing their capacity to sequester GTPases in the cytosol and prevent their membrane localization or interaction with GEFs, adding another layer of regulatory control. A Spectrum of GTPase Families: Diversity in Form and Function The GTPase superfamily is remarkably diverse, comprising distinct families, each with its unique set of members and specialized functions. This volume systematically explores the major families, providing a comprehensive overview of their individual characteristics. The Ras superfamily, perhaps the most widely studied, is a prime example of GTPases at the forefront of signal transduction. The book details the critical roles of Ras proteins in pathways controlling cell growth, proliferation, differentiation, and survival. The intricate signaling networks downstream of Ras, involving effectors such as Raf, RalGEFs, and PI3K, are meticulously mapped out, illustrating how a single GTPase can initiate a cascade of events leading to profound cellular outcomes. The implications of Ras mutations in cancer are also discussed, underscoring their importance in human disease. The Rho family of GTPases, renowned for their profound impact on the actin cytoskeleton, is another major focus. These proteins are central to regulating cell shape, motility, adhesion, and division. The book explores the distinct roles of key Rho family members, including RhoA, Rac1, and Cdc42, in orchestrating the assembly of actin filaments, the formation of lamellipodia and filopodia, and the establishment of cell polarity. The intricate interplay between Rho GTPases and their regulators (GEFs, GAPs, GDIs) is examined in the context of diverse cellular processes such as wound healing, immune cell migration, and neuronal development. The Rab family, essential for vesicular transport and intracellular trafficking, is extensively covered. The book highlights the diverse array of Rab proteins, each localized to specific vesicular compartments and dictating the targeting and fusion of vesicles with their cognate organelles. The mechanisms by which Rabs interact with effector proteins, tethering factors, and SNARE proteins to ensure the fidelity of membrane trafficking are elucidated. The critical roles of Rab proteins in processes ranging from nutrient uptake and secretion to synaptic vesicle release and autophagy are discussed, emphasizing their indispensable nature for cellular organization and function. Other important GTPase families, such as the Arf family (involved in vesicle budding and membrane remodeling) and the Ran family (crucial for nucleocytoplasmic transport), are also presented with detailed explanations of their specific functions and regulatory mechanisms. The book underscores the evolutionary conservation and functional divergence of these families, providing insights into their adaptation to specialized cellular roles. GTPases in Cellular Processes: Orchestrating Life's Dynamics Beyond the specific families, this volume synthesizes the collective impact of GTPases across fundamental cellular processes. Signal Transduction: GTPases serve as pivotal nodes in signal transduction pathways, relaying information from the cell surface to the nucleus and other cellular compartments. Their ability to integrate signals from diverse upstream stimuli and transmit them to downstream effectors makes them indispensable for cellular responsiveness. The book explores how GTPases act as integration points, allowing cells to respond appropriately to environmental cues, growth factors, and stress signals. Cytoskeletal Dynamics: The intricate regulation of the actin cytoskeleton and microtubule network is heavily reliant on GTPases. The Rho family's profound influence on actin organization is a recurring theme, enabling cells to change shape, move, and interact with their surroundings. The book also touches upon the roles of other GTPases in microtubule dynamics, such as the Eg5 motor protein, which plays a critical role in mitotic spindle formation. Membrane Trafficking and Organelle Organization: The meticulous choreography of vesicle formation, movement, and fusion, essential for maintaining cellular homeostasis and carrying out specialized functions, is orchestrated by the Rab family. The book delves into the molecular details of vesicle targeting and fusion, highlighting the roles of Rabs, effectors, and SNAREs in ensuring the proper delivery of proteins and lipids to their destinations. Cell Cycle Progression: GTPases play crucial roles in the precise timing and execution of cell division. The book discusses the involvement of GTPases in the regulation of the cell cycle, from the initiation of DNA replication to the completion of cytokinesis. The dynamic interplay of GTPases in controlling the assembly and disassembly of the mitotic spindle and ensuring accurate chromosome segregation is explored. Cellular Communication and Development: The coordinated behavior of cells within multicellular organisms relies on intricate communication networks, often mediated by GTPases. Their roles in processes like cell migration, adhesion, and differentiation are vital for tissue development, morphogenesis, and immune responses. The book examines how GTPase signaling contributes to the establishment of cell polarity, the formation of intercellular junctions, and the guidance of migratory cells during development. GTPases in Disease: When Regulation Fails The central role of GTPases in cellular regulation means that their dysregulation can have severe consequences, leading to a variety of human diseases. The book dedicates significant attention to the link between aberrant GTPase function and pathology. Cancer: The profound involvement of Ras family GTPases in cell proliferation and survival makes them frequent culprits in cancer development. The book details how oncogenic mutations in Ras proteins can lead to uncontrolled cell growth and resistance to apoptosis. Furthermore, it explores how dysregulation of other GTPases can contribute to tumor invasion, metastasis, and resistance to chemotherapy. Neurological Disorders: The critical roles of GTPases in neuronal development, synaptic plasticity, and vesicular transport make them implicated in a range of neurological conditions. The book discusses how defects in GTPase signaling can contribute to neurodevelopmental disorders, neurodegenerative diseases, and psychiatric conditions. Infectious Diseases: Many pathogens, including viruses and bacteria, have evolved sophisticated strategies to hijack host GTPase signaling pathways for their own replication and spread. The book provides insights into how these pathogens manipulate GTPase functions and how understanding these interactions can lead to novel therapeutic interventions. Conclusion: A Dynamic Frontier In conclusion, this volume provides a comprehensive and detailed exploration of the fascinating world of GTPases. It moves beyond a mere description of individual proteins to illuminate the overarching principles that govern their function, regulation, and impact on cellular life. By meticulously detailing their molecular mechanisms, exploring the diversity of GTPase families, and synthesizing their roles in fundamental cellular processes and disease, this book aims to equip readers with a deep and nuanced understanding of these essential molecular switches. It highlights GTPases not as isolated entities, but as integral components of complex cellular networks, constantly communicating and integrating signals to drive the dynamic processes that define life itself. The continuous discovery of new GTPase functions and their involvement in emerging biological phenomena underscores that this field remains a vibrant and dynamic frontier of biological research.