Effects of Cardiolipin on the Conformational Dynamics of Membrane-Anchored Bcl-xL

Int J Mol Sci. 2021 Aug 30;22(17):9388. doi: 10.3390/ijms22179388.

Abstract

The anti-apoptotic protein Bcl-xL regulates apoptosis by preventing the permeation of the mitochondrial outer membrane by pro-apoptotic pore-forming proteins, which release apoptotic factors into the cytosol that ultimately lead to cell death. Two different membrane-integrated Bcl-xL constructs have been identified: a membrane-anchored and a membrane-inserted conformation. Here, we use molecular dynamics simulations to study the effect of the mitochondrial specific lipid cardiolipin and the protein protonation state on the conformational dynamics of membrane-anchored Bcl-xL. The analysis reveals that the protonation state of the protein and cardiolipin content of the membrane modulate the orientation of the soluble head region (helices α1 through α7) and hence the exposure of its BH3-binding groove, which is required for its interaction with pro-apoptotic proteins.

Keywords: BCL-2 proteins; BH3-binding site; Bcl-xL; apoptotic regulation; cardiolipin; molecular dynamics simulations; protein–membrane interactions.

MeSH terms

  • Apoptosis
  • Cardiolipins / chemistry
  • Cardiolipins / metabolism*
  • Cell Membrane / metabolism*
  • Humans
  • Molecular Dynamics Simulation
  • Protein Conformation*
  • bcl-X Protein / chemistry*
  • bcl-X Protein / metabolism*

Substances

  • BCL2L1 protein, human
  • Cardiolipins
  • bcl-X Protein