Record Details

Studies of the n-end rule pathway in bacteria and mammals [electronic resource] / Tran Minh Tri Vu ; Alexander J. Varshavsky, advisor.
Pasadena, California : California Institute of Technology, 2017.
1 online resource (x, 155 leaves) : digital (7 Mb), illustrations (some color).
CIT theses ; 2017
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.
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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