Mechanism of allosteric regulation of transglutaminase 2 by GTP.
Allosteric regulation is a fundamental mechanism of biological control. Here, we investigated the allosteric mechanism by which GTP inhibits cross-linking activity of transglutaminase 2 (TG2), a multifunctional protein, with postulated roles in receptor signaling, extracellular matrix assembly, and apoptosis. Our findings indicate that at least two components are involved in functionally coupling the allosteric site and active center of TG2, namely (i) GTP binding to mask a conformationally destabilizing switch residue, Arg-579, and to facilitate interdomain interactions that promote adoption of a compact, catalytically inactive conformation and (ii) stabilization of the inactive conformation by an uncommon H bond between a cysteine (Cys-277, an active center residue) and a tyrosine (Tyr-516, a residue located on a loop of the beta-barrel 1 domain that harbors the GTP-binding site). Although not essential for GTP-mediated inhibition of cross-linking, this H bond enhances the rate of formation of the inactive conformer.
Begg
Gillian E
GE
Victor Chang Cardiac Research Institute, University of New South Wales, 384 Victoria Street, Darlinghurst NSW 2010, Australia.
Carrington
Lyle
L
Stokes
Philippa H
PH
Matthews
Jacqueline M
JM
Wouters
Merridee A
MA
Husain
Ahsan
A
Lorand
Laszlo
L
Iismaa
Siiri E
SE
Graham
Robert M
RM
D000494:Allosteric Regulation; D000818:Animals; D001120:Arginine / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D003545:Cysteine / Q000235:genetics / Q000378:metabolism; D004220:Disulfides / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000737:chemistry* / Q000378:metabolism*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D017434:Protein Structure, Tertiary; D051381:Rats; D011503:Transglutaminases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism; D014867:Water / Q000737:chemistry
D004220:Disulfides; C000717609:Tgm2 protein, rat; D014867:Water; D014443:Tyrosine; D006160:Guanosine Triphosphate; D001120:Arginine; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D003545:Cysteine