Synopses & Reviews
A recent review of one of my grant applications commented on the 'rediscovery of tropomyosin'. I was tempted to write back in my rebuttal to the reviewer that I didn't realise it had been lost. Uncharacteristic maturity prevailed and I resisted the temptation, but I was struck by the underlying observation that research on the structure and function of tropomyosin has been somewhat invisible, particularly in terms of the cytoskeleton isoforms. So, how can it be that one of the two major components of the actin filament has been so thoroughly overlooked? I suspect that the answer is disappointingly pedestrian. Whereas the biochemistry of the 1980s revealed the potential of tropomyosin isoforms to diversify the function of actin filaments, the subsequent disenchantment with isoform biology in general in the 1990s inhibited growth of this field. With the development of more sophisticated experimental approaches we are now seeing a growing realisation of the importance of tropomyosin in regulating actin filaments beyond its pivotal role in muscle contraction. The opportunity to edit this book came at a time when we had written several reviews on different aspects of tropomyosin function and I had just finished the background reading for a comprehensive review of tropomyosin biology. I realised that the field was simply beyond the capacity of any one person to do the field justice. Therefore it was a comparatively easy task to look at all the major aspects of tropomyosin biology and identify the leaders in each area. Unfortunately it was not possible for all the major contributors to the field to write chapters; however every chapter is written by an expert in the area. It says something of those who work in the field that everyone who was approached enthusiastically agreed to contribute a chapter. Everyone recognised the importance of pulling the field together through this book and ensuring that each chapter would review the current status of their area and provide an insight into future research directions. I am particularly grateful to Sarah Hitchcock-DeGregori, David Wieczorek, Mario Gimona and David Helfman who worked through the concept of the book with me. They were very generous with their time and suggestions, and this is much appreciated. I am struck by how much I have learned reading these chapters, and the same view has been expressed to me by essentially all authors. All the authors have made the different areas very accessible and provide a current view of the field. It is my expectation that this will serve as the core source on this topic into the foreseeable future. It has captured the first 60 years of work in this field and shone a light into the immediate future. I hope that it is as useful to you as it has been to all of the authors. Finally, I want to thank Ron Landes for the opportunity to edit this book and the team at Landes Bioscience, particularly Cynthia Conomos, Celeste Carlton, Megan Klein and Erin O'Brien, for their help and patience. It has been a great pleasure to work on this with you.
Synopsis
Tropomyosin is one of the two core components of the actin filament and is involved in regulating most if not all functions of these filaments. This book covers all aspects of tropomyosin biology, from gene structure to their role in cell function and disease.
Synopsis
Tropomyosin is one of the two core components of the actin filament and is involved in regulating most if not all functions of these filaments. Tropomyosin has brought together research leaders in this field to review not only what we know but also what the future holds for this field of research. All aspects of tropomyosin biology are covered from gene structure and expression to protein structure, their role in cell function and disease and finally to mechanisms of their function. The book is essential reading for anyone interested in cell structure and function. The actin architectural system is involved in the majority of cellular processes and this book explains how the tropomyosins contribute to this diversity of function. It is not only a comprehensive resource for those working in the field but is also designed to introduce the broader research community to these important molecules.
About the Author
PETER GUNNING, PhD, is Head of the Oncology Research Unit, Department of Pharmacology, School of Medical Sciences, at the University of New South Wales located in Sydney, Australia. The primary focus of his research is the regulation of cell and tissue architecture and its modification in cancer. He is a member of numerous professional organisations and has served on the Boards of the NSW Cancer Council and Bio-Link Partners and as Chairman of the NSW Cancer Council and NSW Cancer Institute Research Committees. Peter received his academic degrees from Monash University, Melbourne, Australia.
Table of Contents
1. Introduction and Historical Perspective............................ 1 Peter Gunning Abstract................................................................................. 1 Introduction........................................................................... 1 Discovery and Context of Tropomyosin Research................ 1 Genes and their Expression (Chapters 2-4).......................... 2 Protein Structure (Chapters 5, 6)........................................... 3 Role in Muscle Function (Chapters 7-9)............................... 3 Tropomyosin in Human Disease (Chapters 10-13).............. 3 Tropomyosin Directed Regulation of the Cytoskeleton (Chapters 14-16)............... 4 Mechanisms of Tropomyosin Function (Chapters 17-21)........................................ 4 Section I. Genes and Their Expression 2. Structure and Evolution of Tropomyosin Genes............. 6 Bernadette Vrhovski, Nadine Thézé and Pierre Thiébaud Abstract.............................................................................. 6 Introduction........................................................................ 6 Structure of Tropomyosin Genes........................................ 7 Evolution of the Tropomyosin Genes................................. 18 Concluding Remarks.......................................................... 23 3. Tropomyosin Exons as Models for Alternative Splicing......................................................... 27 Clare Gooding and Christopher W.J. Smith Abstract............................................................................ 27 Introduction...................................................................... 27 Splicing Mechanism......................................................... 30 Analysis of Alternative Splicing Mechanisms................. 30 ß-Tropomyosin--Tpm2................................................... 32 a-Tropomyosin Exons 2a and 2b..................................... 36 Other Tm Splicing Events................................................ 37 Concluding Remarks: Common Themes, General Insights and Future Directions............................................................................... 38 4. Tropomyosin Gene Expression in Vivo and in Vitro.......... 43 Galina Schevzov and Geraldine O'Neill Abstract.................................................................................. 43 Introduction............................................................................ 43 Temporal Alterations in Tm Isoform Expression during Development................... 44 A common Pattern of Tm expression During Cell Differentiation........................... 47 Functional Significance of Regulated Isoform Expression...................................... 48 Mechanisms Regulating Tm Expression................................. 49 Conclusions............................................................................ 53 References............................................................................. 53 Section II. Protein Structure 5. Tropomyosin: Function Follows Structure........................ 60 Sarah E. Hitchcock-DeGregori Abstract................................................................................. 60 Introduction........................................................................... 60 The Tropomyosin Coiled Coil.............................................. 60 The Tropomyosin Interface: Unstable Regions Interrupt Canonical Coiled Coil ........ 61 The Intermolecular Complex................................................. 64 Actin Binding Sites on Tropomyosin..................................... 67 What Is the Structural Basis of Isoform Specificity?............. 68 Summary and Perspective..................................................... 69 6. Dimerization of Tropomyosins......................................... 73 Mario Gimona Abstract................................................................................ 73 Introduction.......................................................................... 73 Homodimers and Heterodimers............................................ 74 Coiled Coils and Trigger Sequences.................................... 75 N-Terminal Acetylation........................................................ 77 Alanine Clusters and Protein Interaction Sites...................... 81 The C-Terminus in Tm, Formin and Tropomodulin Interactions............................ 82 Conclusions and Perspectives................................................................................ 82 Section III. Role in Muscle Function 7. Cooperative Binding of Tropomyosin to Actin................ 85 Larry S. Tobacman Abstract................................................................................. 85 Introduction--Conjunction Junctions have Anti-Gap Functions............................. 85 The Mechanism of Cooperative Tropomyosin-Actin Binding................................ 86 End-to-End Binding of Tropomyosin in Solution................................................... 86 The Highly Variable End-to-End Overlap Regions of Tropomyosin Isoforms....... 87 The Linear Lattice Conception of Cooperative Tropomyosin Binding to Actin..... 90 Application of the Linear Lattice Formalism--Insights and Mechanistic Implications from Measurements of the Cooperativity of Tropomyosin-Actin Binding.............. 91 Conclusions............................................................................................................ 93 8. Tropomyosin and the Steric Mechanism of Muscle Regulation.......................... 95 William Lehman and Roger Craig Abstract................................................................................ 95 Introduction.......................................................................... 95 Ca2+--Regulation of the Actin-Myosin Interaction............. 98 The Steric-Blocking Model.................................................. 99 Towards a Statistical-Mechanical Understanding of Steric-Regulation............ 103 The Structural Influence of Troponin on Tropomyosin...................................... 104 Perspectives...................................................................................................... 105 9. Role of Tropomyosin in the Regulat ion of Contraction in Smooth Muscle.....110 Steve Marston and M. El-Mezgueldi Abstract................................................................................. 110 Introduction........................................................................... 110 The Components of Smooth Muscle Thin Filaments............. 110 Kinetic Pathway of Myosin-Thin Filament Interaction and Its Regulation......... 114 Regulatory Mechanism of Smooth Muscle Thin Filaments................................ 116 Caldesmon Phosphorylation and the Molecular Mechanism of Thin Filament Regulation.............................................................................. 119 Conclusions........................................................................... 120 Section IV. Tropomyosin in Human Disease 10. Tropomyosin as a Regulat or of Cancer Cell Transformation..................... 124 David M. Helfman, Patrick Flynn, Protiti Khan and Ali Saeed Abstract............................................................................................................. 124 Introduction....................................................................................................... 124 Tm Expression in Transformed Cells and Human Tumors................................ 125 Regulation of Tm Expression in Transformed Cells......................................... 126 The Role of Tropomyosin Expression in Tumor Cell Motility, Invasion and Metastasis......................................................................................................... 127 Tm and the Actin Cytoskeleton in the Regulation of Oncogenic Signaling........ 128 Conclusions...................................................................................................... 129 11. The Role of Tropomyosin in Heart Disease............................................... 132 David F. Wieczorek, Ganapathy Jagatheesan and Sudarsan Rajan The Role of Tropomyosin in Heart Disease..................................................... 132 Tissue and Developmental Specific Expression of Tropomyosin Isoforms in the Heart................................................................................................................ 132 Involvement of Tm in Familial Hypertrophic Cardiomyopathy........................ 134 Involvement of Tm in Dilated Cardiomyopathy............................................... 137 Repairing TM Associated Cardiomyopathies.................................................. 139 Conclusions...................................................................................................... 139 12. Tropomyosins in Skeletal Muscle Diseases............................................... 143 Anthony J. Kee and Edna C. Hardeman Abstract........................................................................................................... 143 Tropomyosins in Skeletal Muscle................................................................... 143 Nemaline Myopathy (NM).............................................................................. 148 TPM3 (a-tropomyosin slow) and NM............................................................. 150 Potential Treatments for NM........................................................................... 151 TPM2 (ß-Tropomyosin), NM and Cap Myopathy........................................... 152 TPM2 and Distal Arthrogryposis type 1 (DA1).............................................. 153 TPM3 and Congenital Fiber Type Disproportion (CFTD).............................. 154 Cardiac Involvement in TPM-Based Myopathies............................................ 154 Conclusions and Perspectives......................................................................... 154 13. Tropomyosins in Human Diseases: Ulcerative Colitis............................. 158 Kiron M. Das and Manisha Bajpai Abstract........................................................................................................... 158 Introduction..................................................................................................... 158 Epidemiology.................................................................................................. 159 Factors Involved in the Pathogenesis of UC.................................................... 159 Tropomyosin (Tm) as an Autoantigen in UC................................................... 160 Conclusion...................................................................................................... 165 Section V. Tropomyosin Directed Regulation of the Cytoskeleton 14. Tropomyosin Function in Yeast............................................................... 168 David Pruyne Abstract......................................................................................................... 168 Conserved Biochemical and Sequence Features of Fungal Tropomyosins......... 168 Establishment of Filament Identity...................................................................... 170 Filament Stabilization and Morphogenesis of Actin-Containing Structures........ 172 Actin Cables and Polarized Cell Growth....................................................... 175 The Contractile Ring and Cell Division......................................................... 178 Conclusions.................................................................................................... 180 15. Isoform Sorting of Tropomyosins................................... 187 Claire Martin and Peter Gunning Abstract................................................................................ 187 Introduction.......................................................................... 187 Sorting of Tm Isoforms in Specific Cell Types.................... 188 Functional Consequences of Tm Sorting.............................. 191 Mechanisms of Tm Sorting.................................................. 192 Lessons from Other Cytoskeletal Proteins........................... 195 Implications of Tm Sorting.................................................. 195 Models of Sorting................................................................ 196 Future Directions................................................................. 198 16. Human Tropomyosin Isoforms in the Regulation of Cytoskeleton Functions....... 201 Jim Jung-Ching Lin, Robbin D. Eppinga, Kerri S. Warren and Keith R. McCrae Abstract................................................................................ 201 Introduction.......................................................................... 201 Human Tropomyosin Gene Organization and Isoforms......... 202 Strategies and Evidence for Differential Localization of Tropomyosins Within the Cells....................................................................................................... 206 Tropomyosin Isoforms Regulate Actin Cytoskeleton Functions.............. 210 Future Directions.................................................................................... 215 Section VI. Mechanisms of Tropomyosin Function 17. Tropomyosins Regulate the Impact of ActinBinding Proteins on Actin Filaments................................................................................................. 223 Uno Lindberg, Clarence E. Schutt, Robert D. Goldman, Maria Nyakern-Meazza, Louise Hillberg, Li-Sophie Zhao Rathje and Staffan Grenklo Abstract.................................................................................................. 223 The Actin Microfilament System............................................................ 223 Cofilin and Arp2/3................................................................................. 224 Gelsolin.................................................................................................. 224 Two Distinct Actin Filament Conformations........................................... 225 Tropomyosin in Lamellipodia................................................................. 226 Cytosolic Tm........................................................................................... 227 Significance of Cytosolic Tm Multimers................................................. 227 High Resolution Crystal Structures of Actin Filaments........................... 228 Concluding Remarks............................................................................... 228 18. Tropomyosin and ADF/cofilin as collaborators and competitors....... 232 Thomas B. Kuhn and James R. Bamburg Abstract.................................................................................................. 232 Introduction............................................................................................. 232 Mechanisms of ADF/cofilin mediated actin turnover.............................. 234 In vitro effects of Tm on AC-induced actin dynamics............................. 236 In vivo evidence for competition and synergy between AC proteins and Tms......... 237 Regulation of AC and role of AC activity in Tm selection and actin binding........... 240 Tm isoforms are functionally distinct....................................................................... 240 Competition and synergy between AC and Tm in selected cellular processes......... 240 Conclusions and perspectives.................................................................................. 245 19. Caldesmon and the Regulation of Cytoskeletal Functions.................................. 250 C.-L. Albert Wang Abstract........................................................................................... 250 Introduction..................................................................................... 250 Genes and Isoforms......................................................................... 251 Cellular Content of h-CaD.............................................................. 253 Tissue Distribution and in Situ Localization................................... 253 Direct Interaction between CaD and Tm........................................ 255 Molecular Shape and Domain Structure......................................... 256 CaD and Tm as Actin-Binding Proteins......................................... 256 Biochemical Properties and Regulatory Functions........................ 259 CaD also Binds to Myosin............................................................. 261 Phosphorylation as a Regulatory Mechanism................................. 262 Nonmuscle CaD and Its Roles During Cell Proliferation and Migration................ 264 Future Directions........................................................................... 265 20. Tropomyosins as Discriminators of Myosin Function............. 273 E. Michael Ostap Abstract......................................................................................... 273 Introduction................................................................................... 273 Myosin Superfamily...................................................................... 274 Tropomyosin Regulation of Myosins............................................ 274 Tropomyosin Regulation of Specific Myosins.............................. 276 Future Directions.......................................................................... 281 21. Tropomodulin/Tropomyosin Interactions Regulate Actin Pointedend Dynamics...................................................................................... 283 Alla S. Kostyukova Abstract........................................................................................ 283 Introduction.................................................................................. 283 Tropomodulin Structure: Tmod1 is an Intrinsically Disordered Protein............... 284 Localization of Binding Sites in the Tmod Molecule............................................ 285 Tm/Tmod Interactions are Isoform Specific......................................................... 287 A model for Tmod/Tm/Actin Complex at the Pointedend..................................... 289 Conclusions.......................................................................................................... 290 Section VII. Conclusion 22. Emerging Issues for Tropomyosin Structure, Regulation, Function and Pathology............................................................................................................. 293 Peter Gunning Abstract............................................................................................................... 293 Introduction......................................................................................................... 293 What is the Composition of the Actin Filament and How is it Assembled?........ 293 What Exactly is Tropomyosin Doing to the Actin Filament?............................... 295 Why are there so Many Isoforms of Tropomyosin?............................................. 295 How do Signalling Cascades Coordinate the Regulation of Tropomyosin Transcription and Splicing with Local Assembly of Different Filament Populations?.............. 296 What are the Prospects for Treating Tropomyosin-Based Diseases?.................. 296