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J. Biol. Chem., Vol. 282, Issue 17, 13123-13132, April 27, 2007

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

BECLIN 1 IS A NOVEL BH3-ONLY PROTEIN^*

From the Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544

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 2.5Å 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.

Received for publication, January 17, 2007 , and in revised form, March 2, 2007.

The atomic coordinates and structure factors (code 2P1L) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by Princeton University and grants from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 609-258-6071; Fax: 609-258-6730; E-mail: ygshi{at}princeton.edu.

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