title: Factor XI anion-binding sites are required for productive interactions with polyphosphate.
abstract: BACKGROUND
  Conversion of factor XI (FXI) to FXIa is enhanced by polymers of inorganic phosphate (polyP). This process requires FXI to bind to polyP. Each FXIa subunit contains anion-binding sites (ABSs) on the apple 3 (A3) and catalytic domains that are required for normal heparin-mediated enhancement of FXIa inhibition by antithrombin.
  
  
  OBJECTIVE
  To determine the importance of FXI ABSs to polyP enhancement of FXI activation.
  
  
  METHODS
  Recombinant FXI variants lacking one or both ABSs were tested in polyP-dependent purified protein systems, plasma clotting assays, and a murine thrombosis model.
  
  
  RESULTS
  In the presence of polyP, activation rates for FXI lacking either ABS were reduced compared with wild-type FXI, and FXI lacking both sites had an even greater defect. In contrast to heparin, polyP binding to FXIa did not enhance inhibition by antithrombin and did not interfere with FXIa activation of FIX. FXI lacking one or both ABSs does not reconstitute FXI-deficient plasma as well as wild-type FXI when polyP was used to initiate coagulation. In FXI-deficient mice, FXI lacking one or more ABSs was inferior to wild-type FXI in supporting arterial thrombus formation.
  
  
  CONCLUSIONS
  The ABSs on FXIa that are required for expression of heparin's cofactor activity during protease inhibition by antithrombin are also required for expression of polyP cofactor activity during FXI activation. These sites may contribute to FXI-dependent thrombotic processes.
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Geng
authors.forename: I M
authors.initials: IM
authors.lastname: Verhamme
authors.forename: S A
authors.initials: SA
authors.lastname: Smith
authors.forename: Q
authors.initials: Q
authors.lastname: Cheng
authors.forename: M
authors.initials: M
authors.lastname: Sun
authors.forename: J P
authors.initials: JP
authors.lastname: Sheehan
authors.forename: J H
authors.initials: JH
authors.lastname: Morrissey
authors.forename: D
authors.initials: D
authors.lastname: Gailani
mesh_terms: D000818:Animals; D000838:Anions; D000991:Antithrombins / Q000737:chemistry; D001665:Binding Sites; D001777:Blood Coagulation; D002417:Cattle; D005164:Factor IX / Q000737:chemistry; D005172:Factor XI / Q000737:chemistry*; D015945:Factor XIa / Q000737:chemistry; D006493:Heparin / Q000737:chemistry; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D000071228:Polyelectrolytes; D011108:Polymers / Q000737:chemistry; D011122:Polyphosphates / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry; D013917:Thrombin / Q000737:chemistry; D013927:Thrombosis / Q000378:metabolism
chemical_list: D000838:Anions; D000991:Antithrombins; D005164:Factor IX; D005172:Factor XI; D015945:Factor XIa; D006493:Heparin; D000071228:Polyelectrolytes; D011108:Polymers; D011122:Polyphosphates; D011994:Recombinant Proteins; D013917:Thrombin
keywords: blood coagulation; factor XI; factor XIa; heparin; polyPhosphates