title: Autoproteolytic activation of pro-caspases by oligomerization.
abstract: Initiation of apopotosis requires the conversion of procaspases to mature caspases. Here we show that oligomerization of pro-caspases is sufficient to induce proteolytic generation of mature caspase subunits and activation of their cell death activity. Deletion of the protein interaction motif DED from pro-caspase-8 greatly suppresses its apoptotic activity. Cell death activity can be restored by oligomerization of pro-caspase-8 protease domains by two heterologous inducible oligomerization systems. Induced oligomerization also activates the apoptotic activity of pro-caspase-1 but not pro-caspase-3. In vitro, oligomerization leads to pro-caspase processing to from the mature caspase subunits; this processing requires the intrinsic caspase activity of zymogens and proceeds via a novel order of cleavage events.
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge 02139, USA.
authors.forename: X
authors.initials: X
authors.lastname: Yang
authors.forename: H Y
authors.initials: HY
authors.lastname: Chang
authors.forename: D
authors.initials: D
authors.lastname: Baltimore
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D020170:Caspase 1; D053148:Caspase 3; D020169:Caspases; D002474:Cell-Free System / Q000201:enzymology; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D019281:Dimerization; D004792:Enzyme Precursors / Q000737:chemistry / Q000378:metabolism*; D053222:Fas Ligand Protein; D006367:HeLa Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection
chemical_list: D004792:Enzyme Precursors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases; D020170:Caspase 1