Abstract
Transglutaminase2 (TG2) is a multi-functional protein involved in various cellular processes, including apoptosis, differentiation, wound healing, and angiogenesis. The malfunction of TG2 causes many human disease including inflammatory disease, celiac disease, neurodegenerative diseases, tissue fibrosis, and cancers. Protein cross-linking activity, which is representative of TG2, is activated by calcium ions and suppressed by GTP. Here, we elucidated the structure of TG2 in complex with its endogenous inhibitor, GTP. Our structure showed why GTP is the optimal nucleotide for interacting with and inhibiting TG2. In addition, sequence comparison provided information describing the evolutionary scenario of GTP usage for controlling the activity of TG2.
Highlights
Transglutaminase2 (TG2) is a multi-functional protein that exerts protein cross-linking activity [1]
It is well known that various TG2 activities are involved in many important cellular processes, including apoptosis [2,3,4], angiogenesis [5,6], wound healing [6,7], and neuronal regeneration [8], and bone development
TG2 has gained attention because it is linked to many human diseases, including inflammatory disease [9], celiac disease [10], neurodegenerative disease [11,12], diabetes [13], tissue fibrosis [14], and cancers [15,16,17]
Summary
Transglutaminase2 (TG2) is a multi-functional protein that exerts protein cross-linking activity [1]. A unique GTP binding site is located in a cleft between the catalytic core and the first b-barrel domain. Our structure showed a conserved GTP binding cleft formed by Phe174, Ser482, Met483, Arg476, Arg478, Arg580, and Tyr583 on TG2.
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