Structural transition in Bcl-xL and its potential association with mitochondrial calcium ion transport.

Structural transition in Bcl-xL and its potential association with mitochondrial calcium ion transport.
Title:
Structural transition in Bcl-xL and its potential association with mitochondrial calcium ion transport.
Other Titles:
Scientific Reports
Keywords:
Publication Date:
29 May 2015
Citation:
Abstract:
Bcl-2 family proteins are key regulators for cellular homeostasis in response to apoptotic stimuli. Bcl-xL, an antiapoptotic Bcl-2 family member, undergoes conformational transitions, which leads to two conformational states: the cytoplasmic and membrane-bound. Here we present the crystal and small-angle X-ray scattering (SAXS) structures of Bcl-xL treated with the mild detergent n-Octyl β-D-Maltoside (OM). The detergent-treated Bcl-xL forms a dimer through three-dimensional domain swapping (3DDS) by swapping helices α6-α8 between two monomers. Unlike Bax, a proapoptotic member of the Bcl-2 family, Bcl-xL is not converted to 3DDS homodimer upon binding BH3 peptides and ABT-737, a BH3 mimetic drug. To validate the functional significance of these conformational rearrangements, we designed Bcl-xL mutants which cannot dimerize and show that these mutants reduced mitochondrial calcium uptake in cells. This illustrates the structural plasticity of Bcl-xL providing insights into the molecular mechanism necessary for Bcl-xL to play a regulatory role in mitochondrial calcium ion transport.
License type:
http://creativecommons.org/licenses/by/4.0/
Funding Info:
Singapore Ministry of Education Tier 2 Grants ARC 4/04, ARC 25/12 (H.S. YOON) and NIH grant R01 CA175003 (C. LI).
Description:
ISSN:
2045-2322
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