title: Inhibition of distant caspase homologues by natural caspase inhibitors.
abstract: Caspases play an important role in the ability of animal cells to kill themselves by apoptosis. Caspase activity is regulated in vivo by members of three distinct protease inhibitor families, two of which, baculovirus p35 and members of the inhibitor of apoptosis (IAP) family, are thought to be caspase specific. However, caspases are members of the clan of cysteine proteases designated CD, which also includes animal and plant legumains, and the bacterial proteases clostripain, gingipain-R and gingipain-K. Since these proteases have been proposed to have a common mechanism and evolutionary origin, we hypothesized that the caspase inhibitors may also regulate these other proteases. We tested this hypothesis by examining the effect of the natural caspase inhibitors on other members of protease clan CD. The IAP family proteins were found to have only a slight inhibitory effect on gingipain-R. The cowpox viral cytokine-response modifier A (CrmA) serpin had no effect on any of the proteases tested but a single point mutation of CrmA (Asp-->Lys) resulted in strong inhibition of gingipain-K. More substantial, with respect to the hypothesis, was the strong inhibition of gingipain-K by wild-type p35. The site in p35, required for inhibition of gingipain-K, was mapped to Lys94, seven residues C-terminal to the caspase inhibitory site. Our data indicate that the virally encoded caspase inhibitors have adopted a mechanism that allows them to regulate disparate members of clan CD proteases.
authors: Program in Apoptosis and Cell Death Research, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: S J
authors: SJ
authors: Snipas
authors: H R
authors: HR
authors: Stennicke
authors: S
authors: S
authors: Riedl
authors: J
authors: J
authors: Potempa
authors: J
authors: J
authors: Travis
authors: A J
authors: AJ
authors: Barrett
authors: G S
authors: GS
authors: Salvesen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016367:Baculoviridae / Q000201:enzymology; D061945:Caspase Inhibitors; D020169:Caspases / Q000737:chemistry*; D003001:Cloning, Molecular; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D017924:Nucleopolyhedroviruses / Q000201:enzymology; D010940:Plant Proteins / Q000037:antagonists & inhibitors; D017354:Point Mutation; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D015843:Serpins / Q000494:pharmacology; D013379:Substrate Specificity; D014764:Viral Proteins / Q000737:chemistry / Q000494:pharmacology; D000099240:Asparaginyl Endopeptidase
chemical_list: D061945:Caspase Inhibitors; D020169:Caspases; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors; D010940:Plant Proteins; D011994:Recombinant Proteins; D015843:Serpins; D014764:Viral Proteins; D000099240:Asparaginyl Endopeptidase; C081618:p35 protein, Nucleopolyhedrovirus; C074641:interleukin-1beta-converting enzyme inhibitor