Interactions between factor XIII and the αC region of fibrinogen

Kerrie Smith, Penelope Adamson, Richard Pease, Jane Brown, Anthony Balmforth, Paul Cordell, Robert Ariens, Helen Phillippou, Peter Grant

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    40 Citations (Scopus)

    Abstract

    Fibrinogen αC residues 242-424 have been shown to have a major regulatory role in the activation of factor XIII-A 2 B 2 (FXIII-A 2 B 2 ); however, the interactions underpinning this enhancing effect have not been determined. Here, we have characterized the binding of recombinant (r)FXIII-A subunit and FXIII-A 2 B 2 with fibrin(ogen) and fibrin αC residues 233-425. Using recombinant truncations of the fibrin αC region 233-425 and surface plasmon resonance, we found that activated rFXIII-A bound αC 233-425 (K d of 2.35 ± 0.09μM) which was further localized to αC 389-403. Site-directed mutagenesis of this region highlighted Glu396 as a key residue for binding of activated rFXIII-A. The interaction was specific for activated rFXIII-A and depended on the calcium-induced conformational change known to occur in rFXIII-A during activation. Furthermore, nonactivated FXIII-A 2 B 2 , thrombin-cleaved FXIII-A 2 B 2 , and activated FXIII-A 2 B 2 each bound fibrin(ogen) and specifically αC region 371-425 with high affinity (K d < 35nM and K d < 31nM, respectively), showing for the first time the potential involvement of the αC region in binding to FXIII-A 2 B 2 . These results suggest that in addition to fibrinogen γ′ chain binding, the fibrin αC region also provides a platform for the binding of FXIII-A 2 B 2 and FXIII-A subunit.

    Original languageEnglish
    Pages (from-to)3460-3468
    Number of pages9
    JournalBlood
    Volume117
    Issue number12
    DOIs
    Publication statusPublished - 24 Mar 2011

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  • Cite this

    Smith, K., Adamson, P., Pease, R., Brown, J., Balmforth, A., Cordell, P., Ariens, R., Phillippou, H., & Grant, P. (2011). Interactions between factor XIII and the αC region of fibrinogen. Blood, 117(12), 3460-3468. https://doi.org/10.1182/blood-2010-10-313601