Synaptic neurexin-neurexophilin complexes : structural insights, mechanistic regulation by alternative splicing, and the search for the molecular organization of the brain
Abstract/Contents
- Abstract
- Abstract Our brains allow us to experience the world, think, and create. Revealing how the brain works is one of the most challenging frontiers in modern science. Yet learning exactly how the brain works is key to understanding cognition and curing neurodegenerative diseases. Recent advances in neurobiology have provided deep insight into how the brain works by deciphering molecular mechanisms of neuronal structure and function (e.g., molecular release of neurotransmitters, specification of synapse formation, and long-term potentiation). However, despite these breakthroughs, we still know very little about how the brain is organized at the molecular level. This work focuses on expanding our molecular understanding of the brain by revealing the molecular details of synaptic neurexin-- neurexophilin interactions. Here, I detail novel crystal structures of neurexin--neurexophilin complexes at near- atomic resolution. These structures consist of neurexophilin-1 in complex with splice variants of the second Laminin-Neurexin-Sex hormone-binding globulin (LNS2) domain of a-neurexin-1. The general architecture of these complexes consists of the b-sandwiches of each molecule essentially fused together to form one large contiguous b-sandwich—a form of protein--protein interaction unlike anything identified before. Furthermore, by combining these structures with biochemical binding experiments, I was able to reveal the molecular mechanism of how alternative splicing of a-neurexin at splice-site #2 modulates the affinity of the neurexin--neurexophilin complexes. These results mark an important step forward in our understanding of neurexin--neurexophilin interactions and how alternative splicing regulates protein--protein interactions. In addition to my structural work, I discuss preliminary binding data from my efforts to discover novel binding partners for neurexophilin-1. These data suggest novel binding partners for neurexophilin-1. Taken together, my structural data and binding data provide new insights into how the brain is likely organized at the molecular level of synaptic neurexin--neurexophilin complexes
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 | 2020; ©2020 |
| Publication date | 2020; 2020 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Wilson, Steven Carl |
|---|---|
| Degree supervisor | Brünger, Axel T |
| Thesis advisor | Brünger, Axel T |
| Thesis advisor | Südhof, Thomas C |
| Thesis advisor | Garcia, K. Christopher |
| Thesis advisor | Shen, Kang, 1972- |
| Degree committee member | Südhof, Thomas C |
| Degree committee member | Garcia, K. Christopher |
| Degree committee member | Shen, Kang, 1972- |
| Associated with | Stanford University, Department of Molecular and Cellular Physiology |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Steven Carl Wilson |
|---|---|
| Note | Submitted to the Department of Molecular and Cellular Physiology |
| Thesis | Thesis Ph.D. Stanford University 2020 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2020 by Steven Carl Wilson
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