Molecular Mechanism of the Cytoplasmic Dynein-Dynactin Motor Complex

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PARENT AWARD PROJECT SUMMARY/ABSTRACT Title: Molecular Mechanism of the Cytoplasmic Dynein-Dynactin Motor Complex Our long-term goal is to elucidate the molecular mechanism of the cytoplasmic dynein-dynactin motor complex, and to define the molecular bases of dynein-related diseases in humans. The microtubule motor cytoplasmic dynein, in cooperation with its regulatory proteins, drives several processes essential to embryonic development, including neuronal proliferation, neuronal migration, and the transport of numerous intracellular cargoes. Thus, it is not surprising dysfunction of dynein contributes to birth defects. A striking example is lissencephaly (LIS), a rare, but devastating brain malformation. Variants of this diseases are caused by loss or mutation of the dynein regulator Lis1. In lissencephaly, neurons fail to migrate properly during development and affected infants’ brains lack the normal gyral folding pattern and layering of the cerebral cortex. These children suffer untreatable epilepsy and severe psychomotor retardation, often dying in the first year of life. Unfortunately, mechanistic insights into dynein function and its regulation by Lis1 are limited, hampering our ability to understand the molecular basis for LIS, and other dynein-linked human diseases. In this proposal, we will combine single-molecule fluorescence and optical tweezers-based force measurements with innovative protein engineering to determine how cytoplasmic dynein in complex with its activator dynactin and the cargo adaptor bicaudal D (BicD), is regulated by Lis1. We will decipher how Lis1 regulates the motion and force generation of the dynein-dynactin-BicD (DDB) motor complex, and determine the effects of human disease mutations on Lis1-DDB function. These studies will provide a new understanding of dynein-linked diseases, and elucidate molecular targets for future therapeutic interventions.