Structural studies on dynein-microtubule complex

Ut Southwestern Medical Center, Dallas TX

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Abstract

DESCRIPTION (provided by applicant): 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.