Dyneins

List of Contributors

Preface

1. Discovery of Dynein and its Properties

1.1. Introduction

1.2. Research at Harvard

1.3. Research at the University of Hawaii

1.4. Semi-Retirement in Berkeley

1.5. The Pluses of Working on a Minus-End-Directed Motor

1.6. Epilogue

2. Evolutionary Biology of Dyneins

2.1. Introduction

2.2. Dynein Classification

2.3. Dynein Evolution in Eukaryotes

2.4. Evolution in the Proto-Eukaryote

2.5. The Origins of Dynein

2.6. Summary

3. The AAA+ Powerhouse – Trying to Understand How it Works

3.1. Introduction

3.2. Sequence analysis of the Dynein AAA+ Domains

3.3. Nucleotide Binding in the Motor Domain

3.4. How are the AAA+ Modules Spatially Arranged?

3.5. Communication of the Motor Domain with the Microtubule-Binding Domain

3.6. Transduction of Local Conformational Changes into Motion

3.7. Conclusion

4. Dynein Motor Mechanisms

4.1. The Dynein Engine Room

4.2. The Linker Arm and Powerstroke

4.3. Microtubule Affinity: Binding at A Distance

4.4. A Three-Part Harmony in A Big Block V-8

5. Structural Analysis of Dynein Intermediate and Light Chains

5.1. Introduction

5.2. Abbreviated Background of Light Chains

5.3. Structure of The Apo Light Chains

5.4. Structure of Liganded Light Chains

5.5. LC8 and Tctex1 Promiscuity

5.6. Light Chain Isoforms

5.7. Mammalian Dynein Intermediate Chains

5.8. Molecular Model of the Light Chain–Intermediate Chain Structure

5.9. Light Chains and Cargo

5.10. Post-Translational Modifications

5.11. The Roles of LC8 and Tctex1 on Dynein

5.12. Summary

6. Biophysics of Dynein In Vivo

6.1. Single-Molecule Properties of Dynein In Vitro

6.2. Multiple-Motor Properties of Dynein In Vitro

6.3. Regulation of Dynein In Vitro

6.4. Regulation of Dynein In Vivo

6.5. Single-Molecule Properties of Dynein In Vivo

6.6. Regulation of Unidirectional Dynein-Based Transport: Vesicular Cargos

6.7. Regulation of Unidirectional Dynein-Based Transport: Large Cargos

6.8. Regulation of Bidirectional Dynein-Based Transport

7. Composition and Assembly of Axonemal Dyneins

7.1. Introduction

7.2. Classes of Dynein Components

7.3. Monomeric Inner Dynein Arms

7.4. Dimeric Inner Dynein Arm I1/f

7.5. Outer Dynein Arms

7.6. Inter-Dynein Linkers

7.7. Properties and Organization of Axonemal Dynein Motor Units

7.8. Core WD-Repeat Intermediate Chains Associated with Oligomeric Motors

7.9. Additional Intermediate Chains

7.10. Core Light Chains Associated with Oligomeric Motors

7.11. Regulatory Components

7.12. Docking Motors onto the Axoneme

7.13. Other Dynein-Associated Components

7.14. Pathways of Axonemal Dynein Assembly and Transport

7.15. Conclusions

8. Organization of Dyneins in the Axoneme

8.1. Introduction

8.2. The History of Methodological Development in Structural Research into Axonemal Dynein

8.3. Dynein Arm Arrangement In Situ

8.4. Inner Dynein Arm Structure In Situ

8.5. Outer Dynein Arm Structure In Situ

8.6. Heterogeneity and Asymmetry of Structure and Arrangement of Dynein in the Axoneme

8.7. Thoughts on Dynein Functions Based on In Situ Structure

8.8. Outlook

9. Genetic Approaches to Axonemal Dynein Function in Chlamydomonas and Other Organisms

9.1. Introduction

9.2. Genetic Studies of Chlamydomonas Axonemal Dyneins

9.3. Genetic Studies in Various Organisms

9.4. Conclusion and Perspective

10. Regulation of Axonemal Outer-Arm Dyneins in Cilia

10.1. Introduction: Structure, Subunit Composition, and Arrangement of Outer-Arm Dynein

10.2. Fundamental Sliding Activity of Outer-Arm Dynein

10.3. Intra-Outer-Arm Dynein (Inter-Heavy Chain) Regulations

10.4. Inter-Outer-Arm Dynein Regulation

10.5. Regulation of Outer-Arm Dynein Activity by External Signals

10.6. Conclusion

11. Control of Axonemal Inner Dynein Arms

11.1. Overview

11.2. Organization of the Inner Dynein Arms in the Axoneme

11.3. Regulation of I1 Dynein by Second Messengers and Phosphorylation

11.4. Current Questions

12. Flagellar Motility and the Dynein Regulatory Complex

12.1. Introduction

12.2. The Central Pair, Radial Spokes, and Dynein Regulatory Complex

12.3. The Dynein Heavy Chain Suppressors

12.4. The Dynein Regulatory Complex and the Inner Dynein Arms

12.5. The Dynein Regulatory Complex and Nexin Link

12.6. Localization of Dynein Regulatory Complex Subunits Within the Nexin Link

12.7. Identification and Characterization of Dynein Regulatory Complex and Nexin Subunits

12.8. Function of the Dynein Regulatory Complex–Nexin Link in Motility and Future Directions

13. Regulation of Dynein in Ciliary and Flagellar Movement

13.1. Introduction

13.2. Basic Features of the Components of Cilia and Flagella

13.3. Regulation of Microtubule Sliding in the Axoneme

13.4. Sliding Microtubule Theory and Bend Formation

13.5. The Mechanism of Oscillation

13.6. Outlook

14. Dynein and Intraflagellar Transport

14.1. Introduction

14.2. Intraflagellar Transport

14.3. Discovery of the Cytoplasmic Dynein 2 Heavy Chain and Early Proposals for its Function

14.4. Identification of Cytoplasmic Dynein 2 as The Intraflagellar Transport Retrograde Motor

14.5. Structure and Subunit Content of Cytoplasmic Dynein 2

14.6. Function of Cytoplasmic Dynein 2 and Retrograde Intraflagellar Transport

14.7. Conclusion

15. Cytoplasmic Dynein Function Defined by Subunit Composition

15.1. Introduction

15.2. Heavy Chain (DYNC1H)

15.3. Light Intermediate Chain (DYNC1LI)

15.4. Intermediate Chain (DYNC1I)

15.5. Dynll (LC8 Light Chain)

15.6. DYNLT (Tctex1 Light Chain)

15.7. DYNLRB (Roadblock Light Chain)

15.8. Conclusion

16. Studies of Lissencephaly and Neurodegenerative Disease Reveal Novel Aspects of Cytoplasmic Dynein Regulation

16.1. Introduction

16.2. Extramolecular Regulation of Cytoplasmic Dynein Force Generation by LIS1 and NudE/NudEL

16.3. Intramolecular Regulation of Dynein Processivity and Implications for Neurodegeneration

16.4. Conclusion

17. Insights into Cytoplasmic Dynein Function and Regulation from Fungal Genetics

17.1. Introduction

17.2. Discoveries of Dynein Function in Spindle Orientation/Nuclear Migration

17.3. Identification of Dynein Regulators Using Fungal Genetics

17.4. Dissecting the Mechanism and Function of the Microtubule-Plus-End Accumulation of Cytoplasmic Dynein

17.5. Understanding The Functions of Various Components of the Dynein and Dynactin Complexes

17.6. Conclusions

18. Genetic Insights into Mammalian Cytoplasmic Dynein Function Provided by Novel Mutations in the Mouse

18.1. Why, and How, We Work with Mice to Learn About Mammalian Genes such as the Dynein Subunits

18.2. Approaches to Working with Mouse Mutants to Learn About Dynein Function

18.3. Accessing Information About Mouse Mutants

18.4. Genetic Background is Important

18.5. Mouse Strains with Mutations in Cytoplasmic Dynein Subunits

18.6. A Further Note on Nomenclature

18.7. An Allelic Series of Mutations in the Mouse Cytoplasmic Dynein Heavy Chain Gene, Dync1h1

18.8. Overall Conclusions from the Dync1h1 Mutant Mice

18.9. The MMTV-DLCS88A Transgenic Mouse

18.10. Using Mouse Genetics to Further Unravel the Role of the Cytoplasmic Dynein Heavy Chain

18.11. Conclusion

19. The Role of Dynactin in Dynein-Mediated Motility

19.1. Introduction

19.2. Structure and Composition of Dynactin

19.3. Known Activities of Dynactin

19.4. Dynactin Function in Dynein-Based Motility

20. Roles of Cytoplasmic Dynein During Mitosis

20.1. Introduction

20.2. Model Systems of Mitotic Dynein

20.3. Spindle Pole Dynein

20.4. Cortical Dynein

20.5. Kinetochore Dynein

20.6. Phosphorylation

20.7. Future Questions

20.8. Conclusions

21. Does Dynein Influence the Non-Mendelian Inheritance of Chromosome 17 Homologs in Male Mice?

21.1. Introduction

21.2. Properties of Tctex1

21.3. Properties of Tctex2

21.4. Properties of Dnahc8

21.5. Chromosomal Deletion Analysis Modifies Lyon’s Model

21.6. Identification of Tcds

21.7. What About Dyneins?

22. Role of Dynein in Viral Pathogenesis

22.1. General Tenets of Virus–Host Interactions

22.2. Blocking Dynein Function in Virus-Infected Cells: Potential Drug Development to Poison Viral Replication Steps

22.3. Direct Interactions with Dynein for Viral Entry: Trafficking Towards the Nucleus by Various Viruses

22.4. Innate Immune Response to Viral Infection

22.5. Dyneins and Stress Granule Assembly: A Novel Concept in Innate Responses to Viral Infection

22.6. Dynein Involvement in Viral Egress and Assembly

22.7. Using Dynein To Traffic to Virus Assembly Domains

22.8. Cell-to-Cell Transmission

22.9. Virus Export from Virus Factories

22.10. Concluding Remarks

23. Cytoplasmic Dynein Dysfunction and Neurodegenerative Disease

23.1. Introduction

23.2. Cytoplasmic Dynein Drives Intracellular Transport in Neurons

23.3. Dynein Function in Developing Neurons

23.4. Dynein Dysfunction in Neurodegeneration

23.5. Dynein Mutations in Model Organisms

23.6. Dynein's Role in the Pathogenesis of Common Neurodegenerative Disease

23.7. Conclusions

24. Dynein Dysfunction as a Cause of Primary Ciliary Dyskinesia and Other Ciliopathies

24.1. Introduction

24.2. Ultrastructure of Motile Cilia

24.3. Outer Dynein Arms

24.4. Inner Dynein Arms

24.5. Ciliopathies

24.6. Primary Cilia Dyskinesia

24.7. Molecular Defects Affecting Outer Dynein Arm Components

24.8. Molecular Defects Affecting Outer and Inner Dynein Arms

24.9. Molecular Defects Affecting the Central Pair and Radial Spokes

24.10. Molecular Defects Affecting Dynein Regulatory Complexes and Inner Dynein Arms

Index