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Studies of the N-end Rule Pathway in Bacteria and Mammals

Citation

Vu, Tran Minh Tri (2017) Studies of the N-end Rule Pathway in Bacteria and Mammals. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z9668B5J. http://resolver.caltech.edu/CaltechTHESIS:07022016-190718870

Abstract

Many intracellular proteins are either conditionally or constitutively short-lived, with in vivo half-lives that can be as brief as a minute or so. The regulated and processive degradation of intracellular proteins is carried out largely by the ubiquitin (Ub)-proteasome system (UPS), in conjunction with molecular chaperones, autophagy, and lysosomal proteolysis. The N-end rule pathway, the first specific pathway of UPS to be discovered, relates the in vivo half-life of a protein to the identity of its N-terminal residue. Physiological functions of the N-end rule pathway are strikingly broad and continue to be discovered. In bacteria and in eukaryotic organelles mitochondria and chloroplasts all nascent proteins bear the pretranslationally formed N-terminal formyl-methionine (fMet) residue. What is the main biological function of this metabolically costly, transient, and not strictly essential modification of N-terminal Met, and why has Met formylation not been eliminated during bacterial evolution? One possibility is that the formyl groups of N-terminal Met in Nt formylated bacterial proteins may signify a proteolytic role of Nt-formylation. My colleagues and I addressed this hypothesis experimentally, as described in Chapter 3 of this thesis.

Among the multitude of biological functions of the mammalian Arg/N-end rule pathway are its roles in the brain, including the regulation of synaptic transmission and the regulation of brain’s G-protein circuits. This regulation is mediated, in part, by the its Ate1-mediated arginylation branch of the Arg/N-end rule pathway. One role of the Ate1 arginyltransferase (R-transferase) is to mediate the conditional degradation of three G-protein down-regulators, Rgs4, Rgs5, and Rgs16. Ate1-/- mice, which lack the Ate1 R-transferase, exhibit a variety of abnormal phenotypes. Chapter 4 describes our studies of neurological abnormalities in Ate1-/- mice (and also in mice that express Ate1 conditionally, upon the addition of doxycycline), with an emphasis on the propensity of these mice to epileptic seizures.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:N-end rules, ubiquitin, degradation, bacteria, mouse, formyl, Ate1
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):
  • Varshavsky, Alexander J.
Thesis Committee:
  • Clemons, William M. (chair)
  • Chan, David C.
  • Shan, Shu-ou
  • Varshavsky, Alexander J.
Defense Date:14 June 2016
Record Number:CaltechTHESIS:07022016-190718870
Persistent URL:http://resolver.caltech.edu/CaltechTHESIS:07022016-190718870
DOI:10.7907/Z9668B5J
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.15698/mic2015.10.231DOIArticle adapted for chapter 2
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:9887
Collection:CaltechTHESIS
Deposited By: Tri Vu
Deposited On:29 Aug 2016 18:30
Last Modified:24 Jul 2018 20:44

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