title: Structural interpretation of 42 mutations causing factor XI deficiency using homology modeling.
abstract: BACKGROUND
  Factor (F)XI is important in the consolidation phase of blood coagulation. The structural effects of mutations causing FXI deficiency have not been well described due to the lack of a structure for FXI.
  
  
  OBJECTIVE
  To develop molecular models of the four apple (Ap) and serine protease (SP) domains in FXI in order to assess the structural effects of published FXI mutations in the light of their phenotypes.
  
  
  METHODS
  The Ap domains were modeled using the NMR structure of an adhesin from Eimeria tenella. The SP domain was modeled using the crystal structure of beta-tryptase.
  
  
  RESULTS
  The effect of 42 mutations causing FXI deficiency was analyzed using homology models for the Ap and SP domains in FXI. Protein misfolding was implicated as the likely structural mechanism of disease in six of 14 mutations in the four Ap domains with Type I phenotypes. Likewise, misfolding was implicated in eight of 14 mutations in the SP domain with Type I phenotypes. Unlike other coagulation factor deficiencies, Type II phenotypes based on a catalytically dysfunctional FXI are uncommon. The structural models indicated that two known Type II mutations in the Ap domains could be correlated with functional defects in substrate or cofactor binding, and likewise four Type II mutations in the SP domain would disrupt the active site.
  
  
  CONCLUSIONS
  New FXI disease-causing mutations can now be structurally characterized to complement phenotypic data, and expression studies can be designed to verify the molecular basis of each deficiency.
authors.affiliation: The Katharine Dormandy Haemophilia Center and Haemostasis Unit, The Royal Free & University College Medical School, London, UK.
authors.forename: N M
authors.initials: NM
authors.lastname: O'Connell
authors.forename: R E
authors.initials: RE
authors.lastname: Saunders
authors.forename: C A
authors.initials: CA
authors.lastname: Lee
authors.forename: D J
authors.initials: DJ
authors.lastname: Perry
authors.forename: S J
authors.initials: SJ
authors.lastname: Perkins
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000941:Antigens / Q000737:chemistry; D001777:Blood Coagulation; D016786:Eimeria tenella; D005173:Factor XI Deficiency / Q000175:diagnosis* / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D012697:Serine Endopeptidases / Q000737:chemistry
chemical_list: D000941:Antigens; D012697:Serine Endopeptidases