Computational analyses of the effect of novel amino acid clusters of human transglutaminase 2 on its structure and function

Transglutaminase 2 (TGM2) is a unique protein of a nine member family with several enzymatic and non-enzymatic activities and interacting partners. Its physiological and pathological roles, however, are not fully understood. Comparative genomic and computational analysis reported here have revealed phylogenetic changes of TGM2 resulting in novel amino acid clusters in humans and other primates, which may impact secondary structure and increase protein stability. These clusters are located in intrinsically disordered regions and via short linear motifs influence interactions with TGM2 partners directly, or through post-translation modification (phosphorylation and N -glycosylation sites). Our data shed new light on the structural background and evolution of TGM2 multi-functionality and points to so far unrevealed biological roles of the enzyme.