Small molecule and protein modulators of microtubule function
Abstract/Contents
- Abstract
- The microtubule cytoskeleton is one of the principal components of eukaryotic cells. Microtubules are involved in the processes of cell division, transport, signaling and differentiation. Furthermore, the microtubule protofilaments can be arranged into a nine-fold symmetric, triplet microtubule structure - the centriole. The centriole has two main roles: to mediate cell division by organizing the spindle, and to mediate signaling by acting as a base for a cilium. In both contexts, microtubules are made up of alpha- and beta- tubulin dimers. The beta-tubulin subunit in the dimer has GTPase activity integral to the properties of microtubules. When the terminal tubulin dimer is in the GDP form, the microtubule is less stable and is usually depolymerized. This process of polymerization and rapid depolymerization of the microtubule is named dynamic instability and is a key property of the microtubule cytoskeleton. This work describes small molecule and protein modulators of microtubule stability and function. Since microtubules play a key role in organizing the mitotic spindle, it has been a key target for cancer therapies. One such molecule, paclitaxel, is a potent microtubule stabilizer that can result in mitotic failure. In this work, a chemical biology approach is used to describe an in silico discovery of new small molecules that bind to the paclitaxel-binding site. The predictions were validated and revealed that commonly used selective estrogen receptor modulators are able to bind microtubules and lead to their stabilization. Centrioles are functionalized by the binding of a variety of protein structures. The exact nature of how these protein structures attach to the microtubules of the centriole have not been characterized. In this work, an evolutionary approach is used to describe potential structural proteins of centriolar accessories. Using cell biological approaches, we investigate the attachment and regulation of a particular centriole accessory, the distal appendages. Overall, this work uses a combination of approaches in answering questions regarding the microtubules cytoskeleton on different scales. Drawing on knowledge from the protein crystal structure of tubulin, new microtubule-binding small molecules were predicted and tested. Furthermore, we investigate the complex microtubule structure, the centriole, and the attachment of its known accessories using both evolutionary and cell biology approaches.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2018; ©2018 |
| Publication date | 2018; 2018 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Cormier, Olga |
|---|---|
| Degree supervisor | Stearns, Tim |
| Thesis advisor | Stearns, Tim |
| Thesis advisor | Feldman, Jessica L |
| Thesis advisor | Kopito, Ron Rieger |
| Thesis advisor | Straight, Aaron, 1966- |
| Degree committee member | Feldman, Jessica L |
| Degree committee member | Kopito, Ron Rieger |
| Degree committee member | Straight, Aaron, 1966- |
| Associated with | Stanford University, Department of Biology |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Olga Cormier. |
|---|---|
| Note | Submitted to the Department of Biology. |
| Thesis | Thesis Ph.D. Stanford University 2018. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2018 by Olga Cormier
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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