Structure and function of factor XI.
Factor XI (FXI) is the zymogen of an enzyme (FXIa) that contributes to hemostasis by activating factor IX. Although bleeding associated with FXI deficiency is relatively mild, there has been resurgence of interest in FXI because of studies indicating it makes contributions to thrombosis and other processes associated with dysregulated coagulation. FXI is an unusual dimeric protease, with structural features that distinguish it from vitamin K-dependent coagulation proteases. The recent availability of crystal structures for zymogen FXI and the FXIa catalytic domain have enhanced our understanding of structure-function relationships for this molecule. FXI contains 4 "apple domains" that form a disk structure with extensive interfaces at the base of the catalytic domain. The characterization of the apple disk structure, and its relationship to the catalytic domain, have provided new insight into the mechanism of FXI activation, the interaction of FXIa with the substrate factor IX, and the binding of FXI to platelets. Analyses of missense mutations associated with FXI deficiency have provided additional clues to localization of ligand-binding sites on the protein surface. Together, these data will facilitate efforts to understand the physiology and pathology of this unusual protease, and development of therapeutics to treat thrombotic disorders.
Emsley
Jonas
J
School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, Nottingham, UK.
McEwan
Paul A
PA
Gailani
David
D
D001777:Blood Coagulation; D001792:Blood Platelets / Q000378:metabolism; D020134:Catalytic Domain; D019281:Dimerization; D004789:Enzyme Activation; D019143:Evolution, Molecular; D005164:Factor IX / Q000737:chemistry; D005172:Factor XI / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D005173:Factor XI Deficiency / Q000097:blood / Q000235:genetics; D005544:Forecasting; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D010980:Platelet Membrane Glycoproteins / Q000502:physiology; D011288:Prekallikrein / Q000737:chemistry / Q000235:genetics; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
D010980:Platelet Membrane Glycoproteins; C077868:coagulation factor XIa receptor, human; D005164:Factor IX; D005172:Factor XI; D011288:Prekallikrein