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Conservation of the extended substrate specificity profiles among homologous granzymes across species.


ABSTRACT: Granzymes are structurally related serine proteases involved in cell death and immunity. To date four out of five human granzymes have assigned orthologs in mice; however for granzyme H, no murine ortholog has been suggested and its role in cytotoxicity remains controversial. Here, we demonstrate that, as is the case for granzyme C, human granzyme H is an inefficient cytotoxin that together with their similar pattern of GrB divergence and functional similarity strongly hint to their orthologous relationship. Besides analyzing the substrate specificity profile of granzyme H by substrate phage display, substrate cleavage susceptibility of human granzyme H and mouse granzyme C was assessed on a proteome-wide level. The extended specificity profiles of granzymes C and H (i.e. beyond cleavage positions P4-P4') match those previously observed for granzyme B. We demonstrate conservation of these extended specificity profiles among various granzymes as granzyme B cleavage susceptibility of an otherwise granzyme H/C specific cleavage site can simply be conferred by altering the P1-residue to aspartate, the preferred P1-residue of granzyme B. Our results thus indicate a conserved, but hitherto underappreciated specificity-determining role of extended protease-substrate contacts in steering cleavage susceptibility.

SUBMITTER: Plasman K 

PROVIDER: S-EPMC3790301 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Conservation of the extended substrate specificity profiles among homologous granzymes across species.

Plasman Kim K   Maurer-Stroh Sebastian S   Ahmad Jamshaid J   Hao Han H   Kaiserman Dion D   Sirota Fernanda L FL   Jonckheere Veronique V   Bird Phillip I PI   Gevaert Kris K   Van Damme Petra P  

Molecular & cellular proteomics : MCP 20130620 10


Granzymes are structurally related serine proteases involved in cell death and immunity. To date four out of five human granzymes have assigned orthologs in mice; however for granzyme H, no murine ortholog has been suggested and its role in cytotoxicity remains controversial. Here, we demonstrate that, as is the case for granzyme C, human granzyme H is an inefficient cytotoxin that together with their similar pattern of GrB divergence and functional similarity strongly hint to their orthologous  ...[more]

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