Histaminylation of glutamine residues is a novel posttranslational modification implicated in G-protein signaling

Posttranslational modifications (PTM) have been shown to be essential for protein function and signaling. Here we report the identification of a novel modification, protein transfer of histamine, and provide evidence for its function in G protein signaling. Histamine, known as neurotransmitter and mediator of the inflammatory response, was found incorporated into mastocytoma proteins. Histaminylation was dependent on transglutaminase II. Mass spectrometry confirmed histamine modification of the small and heterotrimeric G proteins Cdc42, G alpha o1 and G alpha q. The modification was specific for glutamine residues in the catalytic core, and triggered their constitutive activation. TGM2-mediated histaminylation is thus a novel PTM that functions in G protein signaling. Protein alpha monoaminylations, thus including histaminylation, serotonylation, dopaminylation and norepinephrinylation, hence emerge as a novel class of regulatory PTMs. Structured summary of protein interactions: TGM2 enzymaticly reacts CDC42 by enzymatic study (View interaction) TGM2 enzymaticly reacts G alpha 01 by enzymatic study (View interaction) Pak3 physically interacts with CDC42 by solid phase assay (View interaction) TGM2 enzymaticly reacts G alpha q by enzymatic study (View interaction) G alpha 1 binds to Rgs4 by pull down (View interaction) CDC42 physically interacts with Pak3 by pull down (View interaction) (C) 2012 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.