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Related Experiment Videos

A sequential mechanism for exosite-mediated factor IX activation by factor XIa.

Yipeng Geng1, Ingrid M Verhamme, Amanda Messer

  • 1Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee 37232, USA.

The Journal of Biological Chemistry
|September 11, 2012
PubMed
Summary

Factor XIa (fXIa) activates factor IX (fIX) through a novel release-rebind mechanism. The A3 domain of fXIa is crucial for initial binding and efficient activation of fIX.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Hematology

Background:

  • Blood coagulation involves the protease factor XIa (fXIa) activating factor IX (fIX).
  • The precise mechanism and location of exosites involved in fIX activation by fXIa are not fully understood.
  • fXIa comprises four apple domains (A1-A4) and a catalytic domain.

Purpose of the Study:

  • To elucidate the mechanism of factor IX activation by factor XIa.
  • To identify the specific domains of fXIa involved in factor IX binding and cleavage.
  • To investigate the role of exosites and calcium ions in the activation process.

Main Methods:

  • Site-directed mutagenesis of fXIa domains, specifically the A3 and A2 domains.
  • Enzymatic assays to measure kinetic parameters (K(m) and k(cat)) for fIX cleavage.

Related Experiment Videos

  • Comparison of wild-type fXIa with domain-swapped or deleted mutants.

    • Main Results:

    • fIX activation by fXIa occurs via a release-rebind mechanism, with initial cleavage after Arg(145) followed by a second cleavage after Arg(180).
    • The A3 domain of fXIa is essential for initial binding of fIX and fIXα, and its absence significantly impairs catalytic efficiency for the second cleavage.
    • The catalytic efficiency for cleavage after Arg(180) is significantly higher than for cleavage after Arg(145), limiting intermediate accumulation.

    Conclusions:

    • fXIa activates fIX through an exosite- and Ca(2+)-mediated release-rebind mechanism.
    • The A3 domain of fXIa acts as a critical exosite for initial fIX binding and subsequent activation.
    • Conformational changes induced by the first cleavage enhance the efficiency of the second cleavage event.