The cell biology of LRRK2 kinase activation and phosphorylation of Rab GTPases
Abstract/Contents
- Abstract
- LRRK2 kinase mutations cause familial Parkinson's disease and increased phosphorylation of a subset of Rab GTPases. Rab29 recruits LRRK2 to the trans-Golgi and activates it there, yet some of LRRK2's major Rab substrates are not on the Golgi. The second chapter of this thesis describes the cell biology of LRRK2 activation. Unlike other Rab family members, we show that Rab29 binds nucleotide weakly, is poorly prenylated, and is not bound to GDI in the cytosol; nevertheless, Rab29 only activates LRRK2 when it is membrane bound and GTP bound. Mitochondrially anchored, GTP-bound Rab29 is both a LRRK2 substrate and activator, and it drives accumulation of active LRRK2 and phosphorylated Rab10 on mitochondria. Importantly, mitochondrially anchored LRRK2 is much less capable of phosphorylating plasma membrane--anchored Rab10 than soluble LRRK2. These data support a model in which LRRK2 associates with and dissociates from distinct membrane compartments to phosphorylate Rab substrates; if anchored, LRRK2 can modify misdelivered Rab substrates that then become trapped there because GDI cannot retrieve them. Work in the third chapter examines Rab29's possible function and effector proteins. The data demonstrate that there are no significant Golgi structure or retrograde trafficking defects upon Rab29 depletion. Immunoprecipitation followed by mass spectrometry indicates that active Rab29 preferentially binds a calcium channel. Additionally, nucleotide free Rab29 preferentially binds to a GEF complex. These data suggest that Rab29 regulates calcium signaling at the Golgi and may be activated by a GEF complex that also activates Rab7.
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 | 2019; ©2019 |
| Publication date | 2019; 2019 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Gomez, Rachel |
|---|---|
| Degree supervisor | Pfeffer, Suzanne |
| Thesis advisor | Pfeffer, Suzanne |
| Thesis advisor | Harbury, Pehr |
| Thesis advisor | Rohatgi, Rajat |
| Degree committee member | Harbury, Pehr |
| Degree committee member | Rohatgi, Rajat |
| Associated with | Stanford University, Department of Biochemistry. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Rachel C. Gomez. |
|---|---|
| Note | Submitted to the Department of Biochemistry. |
| Thesis | Thesis Ph.D. Stanford University 2019. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2019 by Rachel Gomez
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
Also listed in
Loading usage metrics...