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Updated: Aug 11, 2025

Lighting Up the Pathways to Caspase Activation Using Bimolecular Fluorescence Complementation
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Lighting Up the Pathways to Caspase Activation Using Bimolecular Fluorescence Complementation

Published on: March 5, 2018

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Structures of BIRC6-client complexes provide a mechanism of SMAC-mediated release of caspases

Moritz Hunkeler1,2, Cyrus Y Jin1,2, Eric S Fischer1,2

  • 1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Science (New York, N.Y.)
|February 9, 2023
PubMed

Insights

Inhibitor of apoptosis proteins (IAPs) regulate cell death. This study reveals the structure of BIRC6, explaining how SMAC binding inhibits caspases, offering insights into apoptosis regulation and cancer therapies.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Cell Death Research

Background:

  • Apoptosis regulation is crucial for development and disease prevention.
  • Inhibitor of Apoptosis Proteins (IAPs) control caspases, making them therapeutic targets.
  • Mitochondrial proteins like SMAC and HTRA2 regulate IAPs.

Purpose of the Study:

  • To elucidate the molecular mechanism of BIRC6-mediated caspase inhibition.
  • To understand how SMAC binding releases caspase inhibition by BIRC6.
  • To provide structural insights into IAP regulation by proapoptotic factors.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) of full-length human BIRC6.
  • Structural analysis of BIRC6 in complex with SMAC, caspases, and HTRA2.

Main Results:

  • Determined the architecture of BIRC6 bound to SMAC, caspases, and HTRA2.
  • Revealed the mechanism of BIRC6-mediated caspase inhibition.
  • Demonstrated near-irreversible binding of SMAC to BIRC6, explaining its inhibitory control.

Conclusions:

  • The study provides a molecular understanding of BIRC6 function in apoptosis.
  • SMAC's interaction with BIRC6 highlights a key regulatory mechanism in cell death pathways.
  • Findings offer potential avenues for developing therapeutics targeting IAPs in diseases like cancer.

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