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Mcl-1 and Bok transmembrane domains: Unexpected players in the modulation of apoptosis

Estefanía Lucendo1, Mónica Sancho1, Fabio Lolicato2,3

  • 1Laboratorio de Péptidos y Proteínas, Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain.

Proceedings of the National Academy of Sciences of the United States of America
|October 23, 2020
PubMed

Insights

The Mcl-1 transmembrane domain (TMD) forms self-assemblies and interacts with Bok TMD, influencing apoptosis. Cancer-associated mutations in Mcl-1 TMD enhance its antiapoptotic activity, revealing clinical significance.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The Bcl-2 protein family regulates apoptosis by controlling mitochondrial outer membrane permeabilization.
  • The carboxyl-terminal transmembrane domain (TMD) of some Bcl-2 proteins influences apoptosis.
  • The transmembrane interactome of the antiapoptotic protein Mcl-1 is largely unknown.

Purpose of the Study:

  • To investigate the role and interactions of the Mcl-1 transmembrane domain (TMD).
  • To explore Mcl-1 TMD's function in apoptosis and its relationship with Bok.
  • To assess the impact of cancer-associated Mcl-1 TMD mutations on its activity.

Main Methods:

  • Investigated Mcl-1 TMD homooligomerization and heterooligomerization with Bok TMD.
  • Assessed the antiapoptotic function of Mcl-1 TMD and its competition with full-length Mcl-1.
  • Examined the subcellular localization of Mcl-1 TMD and Bok TMD oligomers.
  • Analyzed the effect of cancer-associated Mcl-1 TMD mutations on protein interactions and function.

Main Results:

  • Mcl-1 TMD forms homooligomers in mitochondrial membranes and induces cell death in a Bok-dependent manner.
  • Mcl-1 TMD competes with full-length Mcl-1 for antiapoptotic function.
  • While Bok TMD oligomers localize to the ER, Mcl-1 and Bok TMD heterooligomers form at the mitochondrial membrane.
  • Mcl-1 coexpression with Bok TMD increases ER-mitochondrial contact sites, suggesting Mcl-1 mediates Bok's mitochondrial targeting.
  • Cancer-associated Mcl-1 TMD mutations enhance antiapoptotic activity by altering TMD interaction patterns.

Conclusions:

  • The Mcl-1 TMD plays a critical role in regulating apoptosis through self-assembly and interaction with Bok.
  • Mcl-1 actively influences Bok localization to mitochondria, impacting cell death pathways.
  • Mcl-1 TMD interactions are clinically relevant, as cancer mutations modulate its antiapoptotic function.
Keywords:
Bcl-2BokMcl-1apoptosistransmembrane

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