Aven, a novel inhibitor of caspase activation, binds Bcl-xL and Apaf-1

Mol Cell. 2000 Jul;6(1):31-40.

Abstract

Bcl-x(L), an antiapoptotic Bcl-2 family member, is postulated to function at multiple stages in the cell death pathway. The possibility that Bcl-x(L) inhibits cell death at a late (postmitochondrial) step in the death pathway is supported by this report of a novel apoptosis inhibitor, Aven, which binds to both Bcl-x(L) and the caspase regulator, Apaf-1. Identified in a yeast two-hybrid screen, Aven is broadly expressed and is conserved in other mammalian species. Only those mutants of Bcl-x(L)that retain their antiapoptotic activity are capable of binding Aven. Aven interferes with the ability of Apaf-1 to self-associate, suggesting that Aven impairs Apaf-1-mediated activation of caspases. Consistent with this idea, Aven inhibited the proteolytic activation of caspases in a cell-free extract and suppressed apoptosis induced by Apaf-1 plus caspase-9. Thus, Aven represents a new class of cell death regulator.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Amino Acid Sequence
  • Animals
  • Apoptosis / physiology
  • Apoptosis Regulatory Proteins
  • Apoptotic Protease-Activating Factor 1
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Caspase 9
  • Caspases / metabolism*
  • Cell Line
  • Dimerization
  • Enzyme Activation
  • Humans
  • Membrane Proteins*
  • Mice
  • Molecular Sequence Data
  • Mutation
  • Protein Binding
  • Protein Structure, Quaternary
  • Proteins / chemistry
  • Proteins / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Tissue Distribution
  • Transfection
  • bcl-X Protein

Substances

  • APAF1 protein, human
  • AVEN protein, human
  • Adaptor Proteins, Signal Transducing
  • Apaf1 protein, mouse
  • Apoptosis Regulatory Proteins
  • Apoptotic Protease-Activating Factor 1
  • BCL2L1 protein, human
  • Bcl2l1 protein, mouse
  • Carrier Proteins
  • Membrane Proteins
  • Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Messenger
  • bcl-X Protein
  • CASP9 protein, human
  • Casp9 protein, mouse
  • Caspase 9
  • Caspases

Associated data

  • GENBANK/AF283508