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TREX1 AUTOIMMUNE DISEASE MUTANTS REVEAL DIMERIC STRUCTURE REQUIREMENTS AND THE C-TERMINAL REGION OF TREX1 CONTROLS CELL LOCALIZATION THROUGH UBIQUITINATION

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abstract
Mutations in the TREX1 3'' exonuclease cause a spectrum of autoimmune disorders in humans. In this study, we elucidate how structural features of TREX1 that are necessary for normal TREX1 biological function are perturbed and lead to disease. TREX1 is a homodimeric enzyme, and the Arg-114 residue contributes to the activity of the opposing protomer by forming bonds across the dimer interface. The mutation R114H is the most commonly found TREX1 mutation in systemic lupus erythematosus (SLE) and Aicardi-Goutières syndrome (AGS). The prevalence of this mutation in autoimmune disease and our finding that this mutation affects the activity of the opposing protomer provides direct evidence that TREX1 activity is dependent on a dimeric structure, and suggests a possible mechanism for modulating TREX1 acitivity in a cell by disrupting dimer contacts.
subject
aicardi-goutieres
autoimmune disease
nucleic acid metabolism
RVCL
systemic lupus
TREX1
contributor
Orebaugh, Clinton David (author)
Perrino, Fred W (committee chair)
Ornelles, David (committee member)
Hollis, Tom (committee member)
Wang, Yuh-Hwa (committee member)
Wilkinson, John C (committee member)
date
2013-06-06T21:19:32Z (accessioned)
2015-06-06T08:30:10Z (available)
2013 (issued)
degree
Biochemistry and Molecular Biology (discipline)
embargo
2015-06-06 (terms)
identifier
http://hdl.handle.net/10339/38548 (uri)
language
en (iso)
publisher
Wake Forest University
title
TREX1 AUTOIMMUNE DISEASE MUTANTS REVEAL DIMERIC STRUCTURE REQUIREMENTS AND THE C-TERMINAL REGION OF TREX1 CONTROLS CELL LOCALIZATION THROUGH UBIQUITINATION
type
Dissertation

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