title: Crystal structure of a procaspase-7 zymogen: mechanisms of activation and substrate binding.
abstract: Apoptosis is primarily executed by active caspases, which are derived from the inactive procaspase zymogens through proteolytic cleavage. Here we report the crystal structures of a caspase zymogen, procaspase-7, and an active caspase-7 without any bound inhibitors. Compared to the inhibitor-bound caspase-7, procaspase-7 zymogen exhibits significant structural differences surrounding the catalytic cleft, which precludes the formation of a productive conformation. Proteolytic cleavage between the large and small subunits allows rearrangement of essential loops in the active site, priming active caspase-7 for inhibitor/substrate binding. Strikingly, binding by inhibitors causes a 180 degrees flipping of the N terminus in the small subunit, which interacts with and stabilizes the catalytic cleft. These analyses reveal the structural mechanisms of caspase activation and demonstrate that the inhibitor/substrate binding is a process of induced fit.
authors.affiliation: Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ 08544, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chai
authors.forename: Q
authors.initials: Q
authors.lastname: Wu
authors.forename: E
authors.initials: E
authors.lastname: Shiozaki
authors.forename: S M
authors.initials: SM
authors.lastname: Srinivasula
authors.forename: E S
authors.initials: ES
authors.lastname: Alnemri
authors.forename: Y
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000595:Amino Acid Sequence; D053179:Caspase 7; D020169:Caspases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity
chemical_list: D004792:Enzyme Precursors; D053179:Caspase 7; D020169:Caspases