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Lighting Up the Pathways to Caspase Activation Using Bimolecular Fluorescence Complementation
08:47

Lighting Up the Pathways to Caspase Activation Using Bimolecular Fluorescence Complementation

Published on: March 5, 2018

Mechanism of XIAP-mediated inhibition of caspase-9

Eric N Shiozaki1, Jijie Chai, Daniel J Rigotti

  • 1Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ 08544, USA.

Molecular Cell
|March 7, 2003
PubMed

Insights

Inhibitor of apoptosis proteins regulate caspases. This study reveals XIAP sequesters caspase-9 as a monomer, preventing its activity and defining a unified caspase activation mechanism.

Area of Science:

  • Cellular biology
  • Biochemistry
  • Structural biology

Background:

  • Inhibitor of apoptosis (IAP) proteins regulate caspase activity.
  • The precise mechanism of initiator caspase-9 inhibition by IAPs is not fully understood.

Purpose of the Study:

  • To elucidate the structural basis of caspase-9 inhibition by XIAP.
  • To define the mechanism by which XIAP regulates caspase-9 activity.

Main Methods:

  • X-ray crystallography to determine the structure of the caspase-9/XIAP-BIR3 complex.
  • Biochemical assays to assess caspase-9 catalytic activity.

Main Results:

  • The crystal structure of caspase-9 in complex with XIAP's BIR3 domain was determined at 2.4 A resolution.
  • XIAP's BIR3 domain forms a heterodimer with monomeric caspase-9.
  • The interaction surface between caspase-9 and BIR3 is also involved in caspase-9 homodimerization.
  • Monomeric caspase-9 is catalytically inactive due to the lack of a homodimerization-dependent supporting element.

Conclusions:

  • XIAP inhibits caspase-9 by sequestering it in an inactive monomeric state.
  • This mechanism provides insight into the regulation of initiator caspases.
  • A unified mechanism for the activation of all caspases is proposed.

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