Mechanism of smoothened regulation by the hedgehog receptor patched
Abstract/Contents
- Abstract
- The Hedgehog (Hh) signaling pathway plays a central role in controling cell growth, survival, fate, and patterning during embryogenesis. The primary receptor for the Hedgehog signal in mammals is the twelve-pass transmembrane protein Patched (PTCH1). In the absence of Hedgehog ligand, PTCH1 constitutively suppresses a downstream seven-pass transmembrane protein Smoothened (SMO), thereby maintaining the quiescence of the pathway. When Hedgehog binds to PTCH1, it blocks its activity, lifting its suppression of SMO and allowing SMO to activate downstream signaling events. Although the genetic relationship between Hh pathway components has been known for over two decades, the fundamental mechanism by which PTCH1 regulates SMO has remained a central question in the Hedgehog signaling field. Based on the observations that PTCH1 is homologous to the Resistance, Nodulation and Division (RND) family of chemiosmotically-driven bacterial transporters, which transport hydrophobic substrates, that SMO is modulated by a series of lipid- and sterol-like ligands, and that PTCH1 suppresses SMO sub-stoichiometrically and does not appear to form a stable complex with SMO, it has been proposed that PTCH1 may regulate SMO by acting as a chemiosmotically driven transmembrane transporter of a lipidic Smo modulator. In this thesis, I investigated the underlying mechanism by which PTCH1 regulates SMO through two parallel strands of research, enabled by novel structures of PTCH1 and SMO: (i) investigating the functional importance of transporter-like structural features of the PTCH1 protein, and (ii) determining how PTCH1-mediated changes in the level of cholesterol in the inner leafet lead to SMO activation
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 | Roberts, Kelsey Jean |
|---|---|
| Degree supervisor | Beachy, Philip Arden |
| Thesis advisor | Beachy, Philip Arden |
| Thesis advisor | Nusse, Roel, 1950- |
| Thesis advisor | Villeneuve, Anne, 1959- |
| Thesis advisor | Wysocka, Joanna, Ph. D |
| Degree committee member | Nusse, Roel, 1950- |
| Degree committee member | Villeneuve, Anne, 1959- |
| Degree committee member | Wysocka, Joanna, Ph. D |
| Associated with | Stanford University, Department of Developmental Biology. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Kelsey Roberts |
|---|---|
| Note | Submitted to the Department of Developmental Biology |
| Thesis | Thesis Ph.D. Stanford University 2020 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2020 by Kelsey Jean Roberts
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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