Maintenance of caspase-3 proenzyme dormancy by an intrinsic "safety catch" regulatory tripeptide.
Caspase-3 is synthesized as a dormant proenzyme and is maintained in an inactive conformation by an Asp-Asp-Asp "safety-catch" regulatory tripeptide contained within a flexible loop near the large-subunit/small-subunit junction. Removal of this "safety catch" results in substantially enhanced autocatalytic maturation as well as increased vulnerability to proteolytic activation by upstream proteases in the apoptotic pathway such as caspase-9 and granzyme B. The safety catch functions through multiple ionic interactions that are disrupted by acidification, which occurs in the cytosol of cells during the early stages of apoptosis. We propose that the caspase-3 safety catch is a key regulatory checkpoint in the apoptotic cascade that regulates terminal events in the caspase cascade by modulating the triggering of caspase-3 activation.
Roy
S
S
Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec, PQ Canada.
Bayly
C I
CI
Gareau
Y
Y
Houtzager
V M
VM
Kargman
S
S
Keen
S L
SL
Rowland
K
K
Seiden
I M
IM
Thornberry
N A
NA
Nicholson
D W
DW
D000595:Amino Acid Sequence; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000737:chemistry / Q000378:metabolism; D002384:Catalysis; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007424:Intracellular Fluid; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000494:pharmacology*; D017433:Protein Structure, Secondary
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D004792:Enzyme Precursors; D010455:Peptides; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases