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Related Experiment Videos

Serpin-protease complexes are trapped as stable acyl-enzyme intermediates

D A Lawrence1, D Ginsburg, D E Day

  • 1American Red Cross Holland Laboratory, Rockville, Maryland 20855, USA.

The Journal of Biological Chemistry
|October 27, 1995
PubMed
Summary

Serine protease inhibitors (serpins) feature unique metastable structures. Upon protease binding, serpins cleave their reactive center loop, forming a stable acyl-enzyme intermediate and driving the complex to its lowest energy state.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Protein Science

Background:

  • Serine protease inhibitors (serpins) possess unique metastable native structures.
  • Their precise mechanism of action as protease inhibitors is debated, with conflicting models.
  • Previous studies proposed trapped complexes in Michaelis-like, tetrahedral, or acyl-enzyme states.

Purpose of the Study:

  • To elucidate the mechanism of serpin-protease complex formation.
  • To resolve the structural state of the stable serpin-protease complex.
  • To propose a unified model for serpin inhibitory action.

Main Methods:

  • Investigated serpin-protease interactions.
  • Analyzed the structural consequences of reactive-center loop (RCL) cleavage.

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  • Utilized biophysical techniques to determine protein conformational changes.

    • Main Results:

    • Demonstrated that serpin RCL cleavage occurs upon target protease association.
    • Identified the formation of an acyl-enzyme intermediate post-cleavage.
    • Observed rapid RCL movement into the protein core, approaching the lowest free energy state.

    Conclusions:

    • Proposed a model where serpins act via an acyl-enzyme intermediate.
    • The drive towards the lowest free energy state traps the protease-inhibitor complex.
    • This mechanism explains the stability of the serpin-protease complex.