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Mechanisms by which Bak and Bax permeabilise mitochondria during apoptosis

Grant Dewson1, Ruth M Kluck

  • 1Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Victoria, Australia.

Journal of Cell Science
|October 2, 2009
PubMed

Insights

Mitochondrial outer membrane permeabilisation (MOMP) is crucial for apoptosis. New findings reveal Bak homo-dimerization via BH3:groove interactions is key to forming pores, offering insights into apoptosis regulation.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Molecular Biology

Background:

  • Mitochondrial outer membrane permeabilisation (MOMP) is a critical, irreversible step in apoptosis.
  • MOMP triggers proteolytic cascades and mitochondrial dysfunction, leading to cell death.
  • Bak and Bax proteins are essential for MOMP, but their pore complex formation and regulation remain unclear.

Purpose of the Study:

  • To elucidate the mechanism of Bak homo-oligomerization in MOMP.
  • To define the role of the Bak BH3 domain and hydrophobic groove in dimer formation.
  • To propose a model for the regulation of apoptosis by Bcl-2 family proteins.

Main Methods:

  • The study focuses on the molecular interactions of Bak during the apoptotic process.
  • It analyzes the transient exposure and binding of the Bak BH3 domain.
  • The research investigates the formation of Bak dimers and higher-order oligomers.

Main Results:

  • A key step in Bak homo-oligomerization involves transient BH3 domain exposure.
  • Activated Bak molecules form symmetric dimers through BH3:groove interactions.
  • Bak dimers further associate via other regions to form higher-order oligomers, likely constituting the MOMP pore.

Conclusions:

  • The BH3:groove interaction provides a fundamental model for Bcl-2 family protein associations.
  • Understanding Bak oligomerization advances knowledge of MOMP regulation.
  • These findings offer new perspectives on controlling apoptotic cell death.

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