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The structure of a transmembrane protein sorting complex

Citation

Chartron, Justin William (2013) The structure of a transmembrane protein sorting complex. Dissertation (Ph.D.), California Institute of Technology. http://resolver.caltech.edu/CaltechTHESIS:10012012-155636249

Abstract

The biogenesis of membrane proteins is an essential process in biology. It requires the protection of hydrophobic transmembrane domains from aggregation in the cytosol as well as targeting to the proper membrane. Tail-anchored (TA) proteins have a single transmembrane helix near their carboxyl termini and require a post-translational mechanism for targeting and insertion. In yeast, the Guided Entry of Tail-anchored proteins (GET) pathway delivers TA proteins to the endoplasmic reticulum (ER). A sorting complex comprising Get4, Get5, and Sgt2 load ER destined TA proteins onto the targeting factor Get3. X-ray crystallography, solution NMR, and small angle X-ray scattering were used to characterize this assembly. Get4 and Get5 form an extended adapter complex. Get4 maintains Get3 in a state competent to receive TA proteins. The N-terminus of Get5 tightly binds Get4, while the C-terminus of Get5 is a homodimerization domain, resulting in a heterotetrameric assembly. A ubiquitin-like domain within Get5 binds the heat-shock protein (HSP) co-chaperone Sgt2, providing a physical link between ER destined TA protein targeting and protein folding pathways. Sgt2 is also an extended homodimeric complex, and can directly bind four major classes of HSPs. The Get4/Get5/Sgt2 sorting complex is multivalent, flexible and the binding of individual components is transient. These results build a model for post-translational protein targeting in eukaryotes that is distinct from other pathways.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:X-ray crystallography; nuclear magnetic resonance; small angle X-ray scattering; membrane proteins; protein targeting; eukaryotes; biochemistry; biophysics
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Biochemistry and Molecular Biophysics
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Clemons, William M.
Thesis Committee:
  • Shan, Shu-ou (chair)
  • Rees, Douglas C.
  • Leadbetter, Jared R.
  • Clemons, William M.
Defense Date:20 September 2012
Funders:
Funding AgencyGrant Number
NIHGM097572
Record Number:CaltechTHESIS:10012012-155636249
Persistent URL:http://resolver.caltech.edu/CaltechTHESIS:10012012-155636249
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1073/pnas.1006036107 DOIArticle adapted for ch. 1
http://dx.doi.org/10.1074/jbc.M111.333252 DOIArticle adapted for ch. 2
http://dx.doi.org/10.1074/jbc.M111.277798DOIArticle adapted for ch. 3
http://dx.doi.org/10.1016/j.celrep.2012.10.010DOIArticle adapted for ch. 4
http://dx.doi.org/10.1016/j.sbi.2012.03.001DOIArticle adapted for Appendix
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:7218
Collection:CaltechTHESIS
Deposited By: Justin Chartron
Deposited On:30 Oct 2012 17:46
Last Modified:01 Oct 2014 18:34

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