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

Sci Rep. 2015 May 29;5:10609. doi: 10.1038/srep10609.

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. We also designed Bcl-xL mutants which cannot dimerize and show that these mutants reduced mitochondrial calcium uptake in MEF cells. This illustrates the structural plasticity in Bcl-xL providing hints toward the probable molecular mechanism for Bcl-xL to play a regulatory role in mitochondrial calcium ion transport.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / chemistry*
  • Calcium / metabolism
  • Ion Transport
  • Mice
  • Mitochondria / metabolism
  • Models, Molecular
  • Molecular Conformation*
  • Mutation
  • Peptide Fragments / chemistry
  • Peptide Fragments / pharmacology
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Multimerization / drug effects
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / pharmacology
  • Scattering, Small Angle
  • bcl-2-Associated X Protein / chemistry
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / metabolism
  • bcl-X Protein / chemistry*
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism

Substances

  • Bax protein (53-86)
  • Peptide Fragments
  • Proto-Oncogene Proteins
  • bcl-2-Associated X Protein
  • bcl-X Protein
  • Calcium