Dynein mutagenesis reveals the molecular basis for dynein regulation in broad spectrum neurological diseases
Date
2020
Authors
Marzo, Matthew G., author
Markus, Steven M., advisor
Bamburg, James R., committee member
DeLuca, Jennifer, committee member
Prasad, Ashok, committee member
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Abstract
Eukaryotic cells rely on cytoskeletal networks to organize materials, transport organelles, give cells shape, and provide locomotion. The cytoskeleton is comprised of many diverse proteins, and three classes of polymeric protein structures are the actin, microtubule, and intermediate filament networks. The microtubule network, and its associated motors, dynein and kinesin, is of interest to the field of neurological disease, due to the prevalence of mutations in the microtubule network in human disease. To better understand the molecular basis for the diseases caused by de novo dynein mutations, we performed a screen of mutants using budding yeast dynein. The results from our experiments present a platform for the molecular dissection of dynein mutations which can be readily applied to new mutations or precisely explore known mutations. The screen-based approach allowed us to identify a new mechanism of yeast dynein regulation, which is autoinhibition of the dynein motor. We demonstrate that this mechanism regulates dynein activity in cells and functions to limit in vivo motor activity in the cytoplasm. Autoinhibition is regulated by Pac1 in yeast, a Lissencephaly-1 homolog, and we demonstrate that Pac1 operates in the dynein autoinhibition pathway by preventing the "closed" autoinhibited state, thereby promoting "open" dynein. This represents an entirely novel function of Pac1/LIS1, and allows us to further refine our model for cortical offloading.
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Subject
dynein
microtubules
yeast cell biology
LIS1
auto inhibition
motor protein