Three-dimensional structure of the apoptosome: implications for assembly, procaspase-9 binding, and activation.
The apoptosome is an Apaf-1 cytochrome c complex that activates procaspase-9. The three-dimensional structure of the apoptosome has been determined at 27 A resolution, to reveal a wheel-like particle with 7-fold symmetry. Molecular modeling was used to identify the caspase recruitment and WD40 domains within the apoptosome and to infer likely positions of the CED4 homology motif and cytochrome c. This analysis suggests a plausible role for cytochrome c in apoptosome assembly. In a subsequent structure, a noncleavable mutant of procaspase-9 was localized to the central region of the apoptosome. This complex promotes the efficient activation of procaspase-3. Therefore, the cleavage of procaspase-9 is not required to form an active cell death complex.
Acehan
Devrim
D
Department of Physiology and Biophysics, Boston University School of Medicine, 700 Albany Street, Boston, MA 02118, USA.
Jiang
Xuejun
X
Morgan
David Gene
DG
Heuser
John E
JE
Wang
Xiaodong
X
Akey
Christopher W
CW
D020816:Amino Acid Motifs; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053477:Apoptotic Protease-Activating Factor 1; D001665:Binding Sites; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D020285:Cryoelectron Microscopy; D003574:Cytochrome c Group / Q000737:chemistry* / Q000378:metabolism; D019281:Dimerization; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism*; D006736:Horses; D006801:Humans; D008958:Models, Molecular; D015388:Organelles / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
C506592:APAF1 protein, human; D053477:Apoptotic Protease-Activating Factor 1; D003574:Cytochrome c Group; D004792:Enzyme Precursors; D011506:Proteins; D011993:Recombinant Fusion Proteins; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases