Microtubule-based motors, dyneins, are nano-meter scale protein machineries and convert chemical energy derived from ATP hydrolysis to mechanical movement. The mechanical movement is employed for various essential intracellular motilities, such as axonal transport, chromosome segregation, and flagellar motility. The importance of dynein functions is underlined by several dynein-related diseases, such as Kartagener's syndrome and amyotrophic lateral sclerosis (ALS). However, little is known about how dynein mutations cause the primary cilia diskinesia or even how dyneins convert chemical energy to mechanical movement. Our long-term goal is to understand the structural basis of energy conversion by dynein and its regulation. To this end we will characterize the structure of dynein-microtubule complexes using cryo-electron microscopy and three-dimensional reconstruction. We have recently obtained two initial structures of dynein-microtubule complexes. One is a low resolution structure of the outer arm dynein-microtubule complex, and another is a medium resolution structure of the microtubule binding domain of dynein, the dynein stalk. Our immediate goals are to refine the structure of the outer arm dynein-microtubule complex to 25Angstroms resolution, and to extend the structure of the dynein stalk structure to 10Angstroms resolution. By studying several structures of these complexes in functionally important states, we would like to elucidate conformational changes essential to the energy conversion, motility and regulation of dynein.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM073847-01A1
Application #
7033453
Study Section
Macromolecular Structure and Function C Study Section (MSFC)
Program Officer
Rodewald, Richard D
Project Start
2006-01-01
Project End
2010-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
1
Fiscal Year
2006
Total Cost
$235,500
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Mizuno, Naoko; Narita, Akihiro; Kon, Takahide et al. (2007) Three-dimensional structure of cytoplasmic dynein bound to microtubules. Proc Natl Acad Sci U S A 104:20832-7
Metlagel, Zoltan; Kikkawa, Yayoi S; Kikkawa, Masahide (2007) Ruby-Helix: an implementation of helical image processing based on object-oriented scripting language. J Struct Biol 157:95-105
Oda, Toshiyuki; Hirokawa, Nobutaka; Kikkawa, Masahide (2007) Three-dimensional structures of the flagellar dynein-microtubule complex by cryoelectron microscopy. J Cell Biol 177:243-52
Narita, Akihiro; Mizuno, Naoko; Kikkawa, Masahide et al. (2007) Molecular determination by electron microscopy of the dynein-microtubule complex structure. J Mol Biol 372:1320-36