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

Bcl‐x L is a potent inhibitor of apoptosis. While Bcl‐x L 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‐x L migrates in a complex...

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Bibliographic Details
Published in:The EMBO journal 2004-05, Vol.23 (10), p.2146-2155
Main Authors: Jeong, Seon-Yong, Gaume, Brigitte, Lee, Yang-Ja, Hsu, Yi-Te, Ryu, Seung-Wook, Yoon, Soo-Han, Youle, Richard J
Format: Article
Language:English
Subjects:
apoptosis
Bad
Bax
Bcl-2
Bcl-xL
dimerization
EMBO07
Filtration
Mutants
Residues
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Summary:Bcl‐x L is a potent inhibitor of apoptosis. While Bcl‐x L 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‐x L migrates in a complex of approximately 50 kDa in the cytosol. Co‐immunoprecipitation experiments indicate that Bcl‐x L in the cytosol forms homodimers. The C‐terminal hydrophobic tails of two Bcl‐x L 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‐x L is longer than that of several monomeric Bcl‐2 family members and is a requisite for the homodimer formation. Bad binding to Bcl‐x L dissociates the homodimers and triggers Bcl‐x L binding to mitochondrial membranes. The C‐terminal tail of Bcl‐x L is also required to mediate Bcl‐x L /Bax heterodimer formation. Both mitochondrial import and antiapoptotic activity of different Bcl‐x L mutants correlate with their ability to form homodimers.
ISSN:0261-4189
1460-2075
DOI:10.1038/sj.emboj.7600225