Crystal Structure of the Bcl-XL-Beclin 1 Peptide Complex

Bcl-2 family proteins are key regulators of apoptosis and have recently been shown to modulate autophagy. The tumor suppressorBeclin 1has beenproposed to coordinate both apoptosis and autophagy through direct interaction with anti-apoptotic family members Bcl-2 and/or Bcl-XL. However, the molecular basis for this interaction remains enigmatic. Herewe report that Beclin 1 contains a conserved BH3 domain, which is both necessary and sufficient for its interaction with Bcl-XL. We also report the crystal structure of a Beclin BH3 peptide in complex withBcl-XL at 2.5 Å resolution. Reminiscent of previously determined Bcl-XL-BH3 structures, the amphipathic BH3 helix of Beclin 1 bound to a conserved hydrophobic groove of Bcl-XL. 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.