CALCIUM-DEPENDENT PROTEOLYSIS AND ISOPEPTIDE BOND FORMATION - CALPAINS AND TRANSGLUTAMINASES

The mechanisms of action and physiological functions of two calcium-activated enzyme families, the calpains and transglutaminases, are discussed: 1. Both enzymes work via a covalent acylenzyme intermediate. Calpains, as other papain-like proteases, have a Cys and His residue in the active site, which in the ground state tend to form a thiolate-imidazolium ion pair. In the active site of tranglutaminases only a Cys residue is usually considered, although data point to the participation of a His. Sequence analysis of transglutaminases reveals two conserved segments with a His in each, either of which may be part of the active site. 2. The physiological functions of the two enzyme families are reviewed. Special attention is given to neuromodulatory (plastic) changes in the nervous system. Two cases are highlighted: a/ The R-subunit of cAMP-dependent protein kinase undergoes limited proteolysis in Drosophila brain, which prolongs kinase action and thus it seems to be part of an intermediate memory process. b/ The covalent crosslinking of synaptic structures by transglutaminase may contribute to lasting information storage, as suggested by the dramatic increase in the amount of "isopeptide" bond in rat hippocampal slices during long-term potentiation (LTP), an experimental model of long-term memory.