title: Crystal structure of procaspase-1 zymogen domain reveals insight into inflammatory caspase autoactivation.
abstract: One key event in inflammatory signaling is the activation of the initiator caspase, procaspase-1. Presented here is the crystal structure of the procaspase-1 zymogen without its caspase recruitment domain solved to 2.05 A. Although the isolated domain is monomeric in solution, the protein appeared dimeric in crystals. The loop arrangements in the dimer provide insight into the first autoproteolytic events that occur during activation by oligomerization. Additionally, in contrast to other caspases, we demonstrate that autoproteolysis at the second cleavage site, Asp316, is necessary for conversion to a stable dimer in solution. Critical elements of secondary structure are revealed in the crystal structure that explain why a dimeric protein is favored after proteolysis at this aspartic acid. Dimer stabilization is concurrent with a 130-fold increase in kcat, the sole contributing kinetic factor to an activated and efficient mediator of inflammation.
authors.affiliation: Department of Protein Chemistry, Genentech, Inc., South San Francisco, California 94080, USA.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Elliott
authors.forename: Lionel
authors.initials: L
authors.lastname: Rouge
authors.forename: Christian
authors.initials: C
authors.lastname: Wiesmann
authors.forename: Justin M
authors.initials: JM
authors.lastname: Scheer
mesh_terms: D020170:Caspase 1 / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D019281:Dimerization; D004789:Enzyme Activation / Q000502:physiology; D004792:Enzyme Precursors / Q000737:chemistry* / Q000378:metabolism; D004795:Enzyme Stability / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000201:enzymology; D018836:Inflammation Mediators / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D020836:Protein Structure, Quaternary / Q000502:physiology; D017433:Protein Structure, Secondary / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology
chemical_list: D004792:Enzyme Precursors; D018836:Inflammation Mediators; D020170:Caspase 1