Alon Monsonego

GTP and Ca²⁺, two well-known modulators of intracellular signaling pathways, control a structural/functional switch between two vital and mutually exclusive activities, cross-linking and G(α) activity, in the same enzyme. The enzyme, a brain-derived tissue-type transglutaminase (TGase), was recently cloned by us in two forms, one of which (s-TGN) lacks a C-terminal region that is present in the other (1-TGN). Immunoreaction with antibodies directed against a peptide present in the C-terminus of 1-TGN but missing in s-TGN suggested that this site, which is located in the C-terminal fourth domain, undergoes conformational changes as a result of interaction between 1-TGN and GTP. Site-directed mutagenesis suggested that the third domain is involved in mediating the inhibition of the cross-linking activity. These results were supported by molecular modeling, which further suggested that domains III and IV both participate in conformational changes leading to the functional switch between the Ca²⁺-dependent cross-linking activity and the G(α) activity.