2:1 Stoichiometry of the CED-4-CED-9 complex and the tetrameric CED-4: insights into the regulation of CED-3 activation.
Four evolutionally conserved proteins -EGL-1, CED-9, CED-4 and CED-3- collectively control the initiation of programmed cell death (PCD) in Caenorhabditis elegans. Activation of CED-3, the cell killing caspase, requires CED-4. The pro-death function of CED-4 is inhibited by the mitochondria-bound CED-9. Crystal structure of the 150-kDa CED-4-CED-9 complex at 2.6 A resolution reveals a 2:1 stoichiometry between CED-4 and CED-9. EGL-1 binding to CED-9 results in the dissociation of CED-4 from the CED-4-CED-9 complex. The freed CED-4 dimer further dimerizes to form a tetramer. Only the CED-4 tetramer, but not dimer or monomer, is capable of activating CED-3. Thus, CED-9 inhibits CED-4-mediated activation of CED-3 by sequestering CED-4 dimer from further dimerization. On the basis of structural and biochemical analyses, working models are proposed to explain the mechanism by which CED-4 facilitates CED-3 activation.
Yan
Nieng
N
Department of Molecular Biology, Princeton University, Lewis Thomas Laboratory, Princeton, New Jersey 08544, USA.
Xu
Yanhui
Y
Shi
Yigong
Y
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017173:Caenorhabditis elegans / Q000737:chemistry* / Q000201:enzymology; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2
D051017:Apoptosis Regulatory Proteins; D029742:Caenorhabditis elegans Proteins; D002135:Calcium-Binding Proteins; C089224:Ced-4 protein, C elegans; C087233:Ced-9 protein, C elegans; D046912:Multiprotein Complexes; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D020169:Caspases; C089223:ced-3 protein, C elegans