Structure of Apaf-1 in the auto-inhibited form: a critical role for ADP.
The pathway of apoptosis is conserved in the three model species: mammals, Drosophila, and C. elegans. The apoptotic protease-activating factor 1, an essential protein conserved in all three species, is responsible for the activation of the initiator caspase-9 in mammalian cells. The structure of the auto-inhibited form of Apaf-1 reveals a critical role for ADP, which serves as an organizing center for four adjoining domains. The ADP-binding pocket contains features that are important for designing other nucleotide analogs. ATP binding is a prerequisite for the formation of the apoptosome. Despite strong sequence conservation between Apaf-1 and its orthologues in Drosophila and C. elegans, it is unclear whether they employ similar mechanisms for their own activation and for activating caspases. Much of the underlying mechanisms remain to be investigated by structural biology and biochemistry.
Bao
Qing
Q
Department of Molecular Biology, Princeton University, Lewis Thomas Laboratory, Princeton, New Jersey 08544, USA.
Riedl
Stefan J
SJ
Shi
Yigong
Y
D000244:Adenosine Diphosphate / Q000737:chemistry*; D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D017209:Apoptosis; D017173:Caenorhabditis elegans; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D029721:Drosophila Proteins / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008958:Models, Molecular; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; C400550:dark protein, Drosophila; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D053453:Caspase 9; D020169:Caspases