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| Subject Categories: Differentiation & Death |
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| The EMBO Journal
(2004) 23, 2146–2155, doi:10.1038/sj.emboj.7600225 Published online 6 May 2004 |
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| Bcl-xL sequesters its C-terminal membrane anchor in soluble, cytosolic homodimers |
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| Seon-Yong Jeong1, 3, Brigitte Gaume1, 3, Yang-Ja Lee1, Yi-Te Hsu2, Seung-Wook Ryu1, Soo-Han Yoon1 and Richard J Youle1 |
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1 Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA 2 Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA To whom correspondence should be addressed Richard J Youle, Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, Room 4N-258, MSC 1414, 10 Center Drive, Bethesda, MD 20892-1414, USA. Tel.: +1 301 496 6628; Fax: +1 301 402 0380; E-mail: youle@helix.nih.gov, youler@ninds.nih.gov 3 These authors contributed equally to this work Received 30 September 2003; Accepted 6 April 2004; Published online 6 May 2004. |
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| Abstract |
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| Bcl-xL is a potent inhibitor of apoptosis. While Bcl-xL can be bound to mitochondria, a substantial fraction, depending on the cell type or tissue, is found in the cytosol of healthy cells. Gel filtration and crosslinking experiments reveal that, unlike monomeric Bax, Bcl-xL migrates in a complex of approximately 50 kDa in the cytosol. Co-immunoprecipitation experiments indicate that Bcl-xL in the cytosol forms homodimers. The C-terminal hydrophobic tails of two Bcl-xL molecules are involved in homodimer formation, and analysis of mutants demonstrates that the C-terminal lysine residue and the G138 residue lining the BH3-binding pocket are required for homodimerization. The flexible loop preceding the C-terminal tail in Bcl-xL is longer than that of several monomeric Bcl-2 family members and is a requisite for the homodimer formation. Bad binding to Bcl-xL dissociates the homodimers and triggers Bcl-xL binding to mitochondrial membranes. The C-terminal tail of Bcl-xL is also required to mediate Bcl-xL/Bax heterodimer formation. Both mitochondrial import and antiapoptotic activity of different Bcl-xL mutants correlate with their ability to form homodimers. |
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| Keywords: apoptosis, Bad, Bax, Bcl-2, Bcl-xL, dimerization |
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