Mutational and functional analyses of the dynein heavy chain indicate the existence of an apical-sistal transport cycle in cells
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The organization, survival, and function of eukaryotic cells depend on intracellular transport governed by the microtubule based molecular motors cytoplasmic dynein and kinesin. Dynein carries out the inward transport of cargos whereas kinesins are responsible for the outward movement. Although intracellular transport is necessary for the function of all cells, polarized cells in particular have specific transport needs due to their asymmetry and elongated shape. These extraordinary requirements necessitate efficient long range microtubule based transport mechanisms. The anterograde transport needs in these cells are satisfied by a variety of kinesins but only a single cytoplasmic dynein fulfills the retrograde transport requirements. Dynein is a megadalton, multiprotein motor complex composed of heavy chains, intermediate chains, light intermediate chains, and light chains. The heavy chains form the force producing motor entity of the dynein complex and the rest of the components are involved in linking dynein to cargoes. The heavy chain has the two functional domains; motor head and a tail. The motor head is responsible for the ATP hydrolysis as well as the microtubule interaction of the dynein complex. The tail domain is involved in the homodimerization of heavy chains as well as interaction with the other dynein subunits. The enormous size and complex mechanochemisty of dynein has complicated our understanding of the functions and regulation of dynein. The study presented here utilized the ascomycete fungus Neurospora crassa in a series of genetic, cell biological and complementing biochemical approaches to study dynein function and regulation. The study is divided into two sections of which the first section will focus on the effects of spontaneous dynein heavy chain mutations on dynein functions in the hyphae of Neurospora crassa along with biochemical analyses of purified dynein from wildtype and a representative mutant strain. The second section focuses on the effect of a mouse neurodegenerative dynein heavy chain mutation on N. crassa dynein function both in vivo and in vitro. The aim of this work is to understand the structure-function relationship and the regulation of dynein.
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Introduction -- Materials and methods -- Characterization of dynein heavy chain mutations in n. crassa -- Analyses of a mouse neurodegenerative dhc mutation in neurospora crassa -- Conclusions
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Ph.D.