Crystal structure of the Bcl-XL-Beclin 1 peptide complex: Beclin 1 is a novel BH3-only protein.
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.
Oberstein
Adam
A
Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA.
Jeffrey
Philip D
PD
Shi
Yigong
Y
D051017:Apoptosis Regulatory Proteins / Q000737:chemistry* / Q000378:metabolism; D001343:Autophagy / Q000502:physiology; D000071186:Beclin-1; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D020836:Protein Structure, Quaternary; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000737:chemistry* / Q000378:metabolism; D051020:bcl-X Protein / Q000737:chemistry* / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; C491997:BECN1 protein, human; C474007:Bax protein (53-86); D000071186:Beclin-1; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D051020:bcl-X Protein