Factor XIa
Coagulation Factor XIaCoagulation Factor XIa
IntroductionIntroduction
Factor XIa is unique protease derived from the activation of the coagulation zymogen, factor XI. Factor XIa partcipates in the procoagulant response via contact activation pathway. Synthesized by the liver similar to most vitamin K-dependent coagulation proteins, the zymogen, factor XI circulates in plasma as a 160 kDa disulfide-linked homodimer in complex with high molecular weight kininogen (HK)(REF). Studies show that factor XI is a substrate for various plasma proteins such as factor XIIa, thrombin, meizothrombin and factor XIa (via autoactivation). Proteolysis of the Arg369-Ile370 bond generates the active enzyme factor XIa which in turn cleaves its substrate factor factor IX to produce the serine protease factor IXa.
Protein StructureProtein Structure
Each dimeric subunit of factor XIa exhibit similar amino acid composition of about 607 residues constituting five main domains. The N-terminus of each subunit contains 4 apple domains (A1, A2, A3 and A4) which are characterized by approximately 90 or 91 amino acid repeats. The C-terminus contain the trypsin-like catalytic domain. Together with Prekallikrein (PK) a monomeric homolog of factor XIa, they belong to the PAN (plasminogen, apple, nematode) module family which all have a conserved N-terminal apple domain. The topology of the apple domain reveals 7 antiparallel β-sheets and an α-helix which fold into a compact structure as opposed to the extended structure found in the vitamin K-dependent serine proteases. A single disulfide likage connects the C- and N-terminals of the dimer whereas two disulfide bond join the heix to the 4β- and 5β-sheets. The apple domains of Factor XIa are tightly linked to each other forming a disk-like structure closed to the base of the C-terminal catalytic domain. This observation is consistent with the high surface areas measurements for the side interfaces between apple domains A1 and A2 (441ÅxÅ) and between A3 and A4 (444ÅxÅ) in contrast to smaller end interfaces between A1 and A4(380ÅxÅ) and between A2 and A3(284ÅxÅ).