GRANZYMES - A VARIETY OF SERINE-PROTEASE SPECIFICITIES ENCODED BY GENETICALLY DISTINCT SUBFAMILIES

Granzymes are a family of granule serine proteases found specifically in the cytotoxic granules of cytotoxic T lymphocytes and natural kille r cells, Granzymes have features that are strongly conserved including : consensus sequences at their N-termini and around the three catalyti c residues, activation from zymogenic forms, and conserved disulphide bridges, However, there is good genetic evidence to suggest that three distinct subfamilies of granzymes have coevolved, These subfamilies a re most strikingly depicted by their distinct chromosomal loci and gen e organization, dividing the granzyme family into subfamilies of the f ollowing: tryptases (human chromosome 5); chymotrypsin-like proteases (human chromosome 14); and a Metase amongst a cluster of elastase-like proteases (human chromosome 19). Modeling and mutational analysis has revealed that each subfamily of granzymes displays special sequence a nd structural features and a proteolytic specificity determined by sub tle modifications to substrate binding pocket residues, It now remains of great interest to determine whether these subfamilies also possess distinct biological-functions. Granzyme B has been shown to play an i mportant role in lymphocyte-mediated target cell apoptosis and the try ptase, granzyme A, has been demonstrated to regulate the clearance of some pox virus infections, The future creation of other granzyme gene knockout mice should elucidate whether other chymotrypsin-like granzym es (C-H) also contribute to target cell apoptosis and whether the thir d subfamily member, natural killer cell-specific Metase, has a distinc t biological function J.