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Designing Conformational Control of Human Tissue Transglutaminase for Applications in Huntington's Disease Research

Berry, Alexandria and Privett, Heidi and Mayo, Stephen (2012) Designing Conformational Control of Human Tissue Transglutaminase for Applications in Huntington's Disease Research. Protein Science, 21 (S1). p. 153. ISSN 0961-8368. http://resolver.caltech.edu/CaltechAUTHORS:20120824-154353922

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Abstract

Human type II transglutaminase (TG2) is an enzyme that exists in two dramatically different conformational states, each with a unique activity. In the open, extended form, the transglutaminase active site is exposed, allowing TG2 to catalyze formation of an isopeptide bond between the sidechain of a peptide-bound glutamine and a primary amine. Upon GTP binding to a separate GTPase active site, TG2 adopts a heavily favored and compact closed conformation, which obstructs the glutaminase active site, and only allows GTPase activity. TG2 has been linked to Huntington's disease, as well as to many other cellular processes, both physiological and pathological. However, TG2's two conformational states, each with its own activity, have made it difficult to elucidate how this enzyme functions in disease progression. In addition, because TG2 heavily prefers the closed state, attempts to screen for inhibitors that may bind the transglutanimase site exposed in the open conformation, and attempts to obtain co-crystals of the enzyme with these inhibitors have proven difficult. The purpose of this study is use computational protein design to engineer TG2 variants locked in either the open or closed conformation. Multistate and single-state design calculations were successful in predicting multiple active variants with 1-4 mutations that preferentially stabilized the open conformation. Closed-locked variants are beginning to be designed. These variants then will be used in Huntington's disease studies to isolate the effects of each of TG2's activities and to assist in rational drug design.


Item Type:Article
Record Number:CaltechAUTHORS:20120824-154353922
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20120824-154353922
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:33530
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:27 Aug 2012 22:30
Last Modified:23 Aug 2016 10:16

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