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

Abstract

Bcl-2 family proteins are key regulators of apoptosis and have recently been shown to modulate autophagy. The tumor sup- pressor Beclin1 has been proposed 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. Herewereport that Beclin 1 contains a conserved BH3 domain, which is both nec- essary and sufficient for its interaction with Bcl-XL. We also report the crystal structure of a Beclin BH3 peptide in complex with Bcl-XL at 2.5A ˚ resolution. Reminiscent of previously deter- mined 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 apo- ptotic signaling. We propose that this putative apoptotic func- tion may be linked to the ability of Beclin 1 to suppress tumor formation in mammals.