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

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.

Grantor dc:publisher

Wake Forest University

Year dc:date.issued

2013

Author dc:creator

• Orebaugh, Clinton David

• aicardi-goutieres

Language dc:language.iso

en

Handle dc:identifier.uri

http://hdl.handle.net/10339/38548

OAI identifier oai:identifier

oai:wakespace.lib.wfu.edu:10339/38548