Crystal Structure of the Bcl-XL-Beclin 1 Peptide Complex: Beclin 1 Is a Novel BH3-only Protein

J Biol Chem. 2007 Apr 27;282(17):13123-32. doi: 10.1074/jbc.M700492200. Epub 2007 Mar 2.

Abstract

Bcl-2 family proteins are key regulators of apoptosis and have recently been shown to modulate autophagy. The tumor suppressor Beclin 1 has been proposed to coordinate both apoptosis and autophagy through direct interaction with anti-apoptotic family members Bcl-2 and/or Bcl-X(L). However, the molecular basis for this interaction remains enigmatic. Here we report that Beclin 1 contains a conserved BH3 domain, which is both necessary and sufficient for its interaction with Bcl-X(L). We also report the crystal structure of a Beclin BH3 peptide in complex with Bcl-X(L) at 2.5A resolution. Reminiscent of previously determined Bcl-X(L)-BH3 structures, the amphipathic BH3 helix of Beclin 1 bound to a conserved hydrophobic groove of Bcl-X(L). These results define Beclin 1 as a novel BH3-only protein, implying that Beclin 1 may have a direct role in initiating apoptotic signaling. We propose that this putative apoptotic function may be linked to the ability of Beclin 1 to suppress tumor formation in mammals.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins / chemistry*
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy / physiology
  • Beclin-1
  • Humans
  • Membrane Proteins / chemistry*
  • Membrane Proteins / metabolism
  • Multiprotein Complexes / chemistry*
  • Multiprotein Complexes / metabolism
  • Peptide Fragments / chemistry*
  • Peptide Fragments / metabolism
  • Protein Structure, Quaternary
  • Proto-Oncogene Proteins / chemistry*
  • Proto-Oncogene Proteins / metabolism
  • Tumor Suppressor Proteins / chemistry*
  • Tumor Suppressor Proteins / metabolism
  • bcl-X Protein / chemistry*
  • bcl-X Protein / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • BCL2L1 protein, human
  • BECN1 protein, human
  • Bax protein (53-86)
  • Beclin-1
  • Membrane Proteins
  • Multiprotein Complexes
  • Peptide Fragments
  • Proto-Oncogene Proteins
  • Tumor Suppressor Proteins
  • bcl-X Protein

Associated data

  • PDB/2P1L