The dimeric structure of factor XI and zymogen activation.

Yipeng Geng, Ingrid M. Verhamme, Stephen B. Smith, Mao Fu Sun, Anton Matafonov, Qiufang Cheng, Stephanie A. Smith, James H. Morrissey, David Gailani

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Factor XI (fXI) is a homodimeric zymogen that is converted to a protease with 1 (1/2-fXIa) or 2 (fXIa) active subunits by factor XIIa (fXIIa) or thrombin. It has been proposed that the dimeric structure is required for normal fXI activation. Consistent with this premise, fXI monomers do not reconstitute fXI-deficient mice in a fXIIa-dependent thrombosis model. FXI activation by fXIIa or thrombin is a slow reaction that can be accelerated by polyanions. Phosphate polymers released from platelets (poly-P) can enhance fXI activation by thrombin and promote fXI autoactivation. Poly-P increased initial rates of fXI activation 30- and 3000-fold for fXIIa and thrombin, respectively. FXI monomers were activated more slowly than dimers by fXIIa in the presence of poly-P. However, this defect was not observed when thrombin was the activating protease, nor during fXI autoactivation. The data suggest that fXIIa and thrombin activate fXI by different mechanisms. FXIIa may activate fXI through a trans-activation mechanism in which the protease binds to 1 subunit of the dimer, while activating the other subunit. For activation by thrombin, or during autoactivation, the data support a cis-activation mechanism in which the activating protease binds to and activates the same fXI subunit.

Original languageEnglish
Pages (from-to)3962-3969
Number of pages8
JournalBlood
Volume121
Issue number19
DOIs
Publication statusPublished - 9 May 2013
Externally publishedYes

Fingerprint

Factor XI
Enzyme Precursors
Factor XIIa
Chemical activation
Thrombin
Peptide Hydrolases
Dimers
Monomers
Platelets
Polymers
Thrombosis

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Geng, Y., Verhamme, I. M., Smith, S. B., Sun, M. F., Matafonov, A., Cheng, Q., ... Gailani, D. (2013). The dimeric structure of factor XI and zymogen activation. Blood, 121(19), 3962-3969. https://doi.org/10.1182/blood-2012-12-473629

The dimeric structure of factor XI and zymogen activation. / Geng, Yipeng; Verhamme, Ingrid M.; Smith, Stephen B.; Sun, Mao Fu; Matafonov, Anton; Cheng, Qiufang; Smith, Stephanie A.; Morrissey, James H.; Gailani, David.

In: Blood, Vol. 121, No. 19, 09.05.2013, p. 3962-3969.

Research output: Contribution to journalArticle

Geng, Y, Verhamme, IM, Smith, SB, Sun, MF, Matafonov, A, Cheng, Q, Smith, SA, Morrissey, JH & Gailani, D 2013, 'The dimeric structure of factor XI and zymogen activation.', Blood, vol. 121, no. 19, pp. 3962-3969. https://doi.org/10.1182/blood-2012-12-473629
Geng Y, Verhamme IM, Smith SB, Sun MF, Matafonov A, Cheng Q et al. The dimeric structure of factor XI and zymogen activation. Blood. 2013 May 9;121(19):3962-3969. https://doi.org/10.1182/blood-2012-12-473629
Geng, Yipeng ; Verhamme, Ingrid M. ; Smith, Stephen B. ; Sun, Mao Fu ; Matafonov, Anton ; Cheng, Qiufang ; Smith, Stephanie A. ; Morrissey, James H. ; Gailani, David. / The dimeric structure of factor XI and zymogen activation. In: Blood. 2013 ; Vol. 121, No. 19. pp. 3962-3969.
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