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  • The EMBO Journal (2004) 23, 2146 - 2155
  • doi:10.1038/sj.emboj.7600225

Published online: 6 May 2004

Bcl-xL sequesters its C-terminal membrane anchor in soluble, cytosolic homodimers

Seon-Yong Jeong1,a, Brigitte Gaume1,a, Yang-Ja Lee1, Yi-Te Hsu2, Seung-Wook Ryu1, Soo-Han Yoon1 and Richard J Youle1

  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

Correspondence to:

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

aThese authors contributed equally to this work

Received 30 September 2003; Accepted 6 April 2004

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.

  • Keywords:

    • apoptosis,
    • Bad,
    • Bax,
    • Bcl-2,
    • Bcl-xL,
    • dimerization