Record Details

Title:
Studies of the n-end rule pathway in bacteria and mammals [electronic resource] / Tran Minh Tri Vu ; Alexander J. Varshavsky, advisor.
Author(s):
Imprint:
Pasadena, California : California Institute of Technology, 2017.
Description:
1 online resource (x, 155 leaves) : digital (7 Mb), illustrations (some color).
Subject(s):
Series:
CIT theses ; 2017
Summary:
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.
Note:
Advisor and committee chair names found in the thesis' metadata record in the digital repository.
Dissertation note:
Thesis (Ph. D.) -- California Institute of Technology, 2017.
Bibliography, etc. note:
Includes bibliographical references.
Linked resources:
Caltech Connect
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 Record created 2017-11-08, last modified 2018-09-17


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