Citation
Hazu, Masami (2025) Mechanistic Studies of Membrane Protein Biogenesis at the ER and Mitochondria. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/snc5-jf69. https://resolver.caltech.edu/CaltechTHESIS:02082025-232945882
Abstract
Eukaryotic cells are organized into membrane-enclosed compartments with elaborate networks of integral membrane proteins. From synthesis, localization, and insertion into designated cellular membranes, to proper folding and assembly of the membrane proteins, the successful biogenesis of membrane proteins is crucial for defining the organellar compartments and for overall proteostasis. Recent advances in the field of membrane protein biogenesis in both the endoplasmic reticulum (ER) and the mitochondria have identified novel machineries involved in the membrane insertion step. These are the ER membrane protein complex (EMC) at the ER and the mitochondrial carrier homolog 2 (MTCH2) at the outer mitochondrial membrane (OMM). In this thesis, we employ a combination of biochemical, cell biological, structural, and genetic techniques to explore in mechanistic detail the insertase function of the EMC and MTCH2 at the molecular level. In the first part of the thesis, our work on the EMC maps out the pathway of a tail-anchored (TA) protein through the insertase and revealed a selectivity filter that provides the biochemical basis for how the EMC protects compartment integrity. The selectivity filter of the EMC limits TA protein mislocalization and prevents topological errors of multi-pass membrane proteins. In the second part, ongoing work on MTCH2 reveals the absence of a prominent selectivity mechanism and provides insight into a regulatory mechanism of MTCH2, which seems to be conserved across metazoan MTCH2 homologs.
| Item Type: | Thesis (Dissertation (Ph.D.)) | |||||||||
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| Subject Keywords: | membrane protein; protein biogenesis; membrane insertion; endoplasmic reticulum; mitochondria | |||||||||
| Degree Grantor: | California Institute of Technology | |||||||||
| Division: | Biology and Biological Engineering | |||||||||
| Major Option: | Biology | |||||||||
| Thesis Availability: | Not set | |||||||||
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| Defense Date: | 4 December 2024 | |||||||||
| Record Number: | CaltechTHESIS:02082025-232945882 | |||||||||
| Persistent URL: | https://resolver.caltech.edu/CaltechTHESIS:02082025-232945882 | |||||||||
| DOI: | 10.7907/snc5-jf69 | |||||||||
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| Default Usage Policy: | No commercial reproduction, distribution, display or performance rights in this work are provided. | |||||||||
| ID Code: | 16987 | |||||||||
| Collection: | CaltechTHESIS | |||||||||
| Deposited By: | Masami Hazu | |||||||||
| Deposited On: | 18 Feb 2025 19:22 | |||||||||
| Last Modified: | 18 Feb 2025 19:22 |
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