title: Calcium blocks formation of apoptosome by preventing nucleotide exchange in Apaf-1.
abstract: Apaf-1 plays an essential role in apoptosis. In the presence of cytochrome c and dATP, Apaf-1 assembles into an oligomeric apoptosome, which is responsible for the activation of procaspase-9 and the maintenance of the enzymatic activity of the processed caspase-9. Regulation of apoptosome assembly by other cellular factors is poorly understood. Here we report that physiological concentrations of calcium ion negatively affect the assembly of apoptosome by inhibiting nucleotide exchange in the monomeric, autoinhibited Apaf-1 protein. Consequently, calcium blocks the ability of Apaf-1 to activate caspase-9. These observations suggest an important role of calcium homeostasis on the Apaf-1-dependent apoptotic pathway.
authors.affiliation: Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Bao
authors.forename: Wenyun
authors.initials: W
authors.lastname: Lu
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Rabinowitz
authors.forename: Yigong
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000227:Adenine Nucleotides / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D053478:Apoptosomes / Q000187:drug effects* / Q000378:metabolism*; D053477:Apoptotic Protease-Activating Factor 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology*; D053453:Caspase 9 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006706:Homeostasis; D006801:Humans; D066298:In Vitro Techniques; D008954:Models, Biological; D011487:Protein Conformation / Q000187:drug effects; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: C506592:APAF1 protein, human; D000227:Adenine Nucleotides; D053478:Apoptosomes; D053477:Apoptotic Protease-Activating Factor 1; D011994:Recombinant Proteins; D053453:Caspase 9; D002118:Calcium