Functional characterization of naturally occurring mutant transglutaminase 2
Salter, Neil William
Transglutaminase 2 (TG2) is a functionally and structurally complex ubiquitous protein. TG2 has Ca2+-dependent transamidating activity, can bind and hydrolyze ATP/GTP, function as a G-protein in intracellular signaling, and has reported kinase activity. TG2 knockout mice are observed to have impaired glucose-stimulated insulin secretion (GSIS). Three naturally occurring mutations, including Met330Arg, Ile331Asn, and Asn333Ser, have been reported in the TG2 protein and observed to be related with maturity onset diabetes of the young (MODY). Overexpression of the naturally occurring Myc-tag mutants in INS-1E cells generated a loss in GSIS compared to wild type-TG2 overexpression. Each mutant was shown to have diminished transamidation and kinase activities, along with altered GTP-binding which was responsive to glucose stimulation. Naturally occurring mutations in TG2 impact the transamidation, kinase, and GTP-binding functions of TG2. The GTP-binding function of TG2 has a significant impact on GSIS from pancreatic beta cells in addition to its transamidating activity.