Dynein mutagenesis reveals the molecular basis for dynein regulation in broad spectrum neurological diseases
| dc.contributor.author | Marzo, Matthew G., author | |
| dc.contributor.author | Markus, Steven M., advisor | |
| dc.contributor.author | Bamburg, James R., committee member | |
| dc.contributor.author | DeLuca, Jennifer, committee member | |
| dc.contributor.author | Prasad, Ashok, committee member | |
| dc.date.accessioned | 2020-06-22T11:53:40Z | |
| dc.date.available | 2022-06-15T11:53:40Z | |
| dc.date.issued | 2020 | |
| dc.description.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. | |
| dc.format.medium | born digital | |
| dc.format.medium | doctoral dissertations | |
| dc.identifier | Marzo_colostate_0053A_15915.pdf | |
| dc.identifier.uri | https://hdl.handle.net/10217/208537 | |
| dc.language | English | |
| dc.language.iso | eng | |
| dc.publisher | Colorado State University. Libraries | |
| dc.relation.ispartof | 2020- | |
| dc.rights | Copyright and other restrictions may apply. User is responsible for compliance with all applicable laws. For information about copyright law, please see https://libguides.colostate.edu/copyright. | |
| dc.subject | dynein | |
| dc.subject | microtubules | |
| dc.subject | yeast cell biology | |
| dc.subject | LIS1 | |
| dc.subject | auto inhibition | |
| dc.subject | motor protein | |
| dc.title | Dynein mutagenesis reveals the molecular basis for dynein regulation in broad spectrum neurological diseases | |
| dc.type | Text | |
| dcterms.embargo.expires | 2022-06-15 | |
| dcterms.embargo.terms | 2022-06-15 | |
| dcterms.rights.dpla | This Item is protected by copyright and/or related rights (https://rightsstatements.org/vocab/InC/1.0/). You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s). | |
| thesis.degree.discipline | Biochemistry and Molecular Biology | |
| thesis.degree.grantor | Colorado State University | |
| thesis.degree.level | Doctoral | |
| thesis.degree.name | Doctor of Philosophy (Ph.D.) |
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