The mechanism underlying activation of factor IX by factor XIa

Gailani, David; Geng, Yipeng; Verhamme, Ingrid; Sun, Mao-fu; Bajaj, S. Paul; Messer, Amanda; Emsley, Jonas

Abstract

Factor XI (fXI) is the zymogen of a plasma protease, factor XIa (fXIa), that contributes to thrombin generation during blood coagulation by proteolytic conversion of factor IX (fIX) to factor IXaβ (fIXaβ). There is considerable interest in fXIa as a therapeutic target because it contributes to thrombosis, while serving a relatively minor role in hemostasis. FXI/XIa has a distinctly different structure than other plasma coagulation proteases. Specifically, the protein lacks a phospholipid-binding Gla-domain, and is a homodimer. Each subunit of a fXIa dimer contains four apple domains (A1 to A4) and one trypsin-like catalytic domain. The A3 domain contains a binding site (exosite) that largely determines affinity and specificity for the substrate fIX. After binding to fXIa, fIX undergoes a single cleavage to form the intermediate fIXα. FIXα then rebinds to the A3 domain to undergo a second cleavage, generating fIXaβ. The catalytic efficiency for the second cleavage is ~ 7-fold greater than that of the first cleavage, limiting fIXα accumulation. Residues at the N-terminus and C-terminus of the fXIa A3 domain likely form the fIX binding site. The dimeric conformation of fXIa is not required for normal fIX activation in solution. However, monomeric forms of fXI do not reconstitute fXI-deficient mice in arterial thrombosis models, indicating the dimer is required for normal function in vivo. FXI must be a dimer to be activated normal by the protease fXIIa. It is also possible that the dimeric structure is an adaptation that allows fXI/XIa to bind to a surface through one subunit, while binding to its substrate fIX through the other.

Citation

Gailani, D., Geng, Y., Verhamme, I., Sun, M.-F., Bajaj, S. P., Messer, A., & Emsley, J. (2014). The mechanism underlying activation of factor IX by factor XIa. Thrombosis Research, 133(Supplement 1), S48-S51. https://doi.org/10.1016/j.thromres.2014.03.020

• Journal Article Type: Article
• Acceptance Date: May 1, 2014
• Online Publication Date: Apr 18, 2014
• Publication Date: 2014-05
• Deposit Date: Sep 13, 2017
• Journal: Thrombosis Research
• Print ISSN: 0049-3848
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 133
• Issue: Supplement 1
• Pages: S48-S51
• DOI: https://doi.org/10.1016/j.thromres.2014.03.020
• Keywords: Factor XIa; Factor IX; Exosite
• Public URL: https://nottingham-repository.worktribe.com/output/1098381
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0049384814001455?via%3Dihub
• PMID: 00033726