NDLI: NMR Structural Investigation of the Mitochondrial Outer Membrane Protein VDAC and its Interaction with Anti-apoptotic Bcl-xL †

Content Provider	PubMed Central
Author	Malia, Thomas J. Wagner, Gerhard
Abstract	Bcl-2 family proteins are essential regulators of cell death and exert their primary pro- or anti-apoptotic roles at the mitochondrial outer membrane. Previously, pro- and anti-apoptotic Bcl-2 proteins have been shown to interact with the voltage dependent anion channel (VDAC) of the outer mitochondrial membrane. VDAC is a 283-residue integral membrane protein that forms an aqueous pore in the outer mitochondrial membrane, through which metabolites and other small molecules pass between the cytosol and intermembrane space. The essential life-sustaining function of VDAC in metabolite trafficking is believed to be regulated by proteins of the Bcl-2 family. The protective role of anti-apoptotic Bcl-xL may be through its interaction with VDAC. Here, VDAC has been expressed, purified, and refolded into a functional form amenable to NMR studies. Various biophysical experiments indicate that micelle-bound VDAC is in intermediate exchange between monomer and trimer. Using NMR spectroscopy, gel filtration, and chemical cross-linking we obtained direct evidence for binding of Bcl-xL to VDAC in a detergent micelle system. The VDAC-interacting region of Bcl-xL was characterized by NMR with chemical shift perturbation and transferred cross saturation. The interaction region was mapped to a putative helical hairpin motif of Bcl-xL that was found to insert into detergent micelles. Our results suggest that Bcl-xL can bind to 1 or 2 VDAC molecules forming heterodimers and heterotrimers. Our characterization of the VDAC/Bcl-xL complex offer initial structural insight into the role of anti-apoptotic Bcl-xL in regulating apoptotic events in the mitochondrial outer membrane.
Related Links	http://dx.doi.org/10.1021/bi061577h
Ending Page	525
Page Count	12
Starting Page	514
File Format	PDF
ISSN	00062960
e-ISSN	15204995
Journal	Biochemistry
Issue Number	2
Volume Number	46
Language	English
Publisher Date	2007-01-01
Access Restriction	Open
Subject Keyword	Biochemistry Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Biochemistry

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