Factor XIa: Difference between revisions

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==Coagulation Factor XIa==

===Introduction===

'''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>PMID:915004</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 <scene name='Sandbox/Arg369-ile370/1'> Arg369-Ile370</scene> bond generates the active enzyme factor XIa which in turn cleaves its substrate factor IX to produce the serine protease factor IXa.

'''Factor XIa''' is a <scene name='Sandbox/Disulfides/1'>disulfide</scene> linked-dimer of similar amino acid composition of approximately 625 residues. The first 18 amino acid residues constitute the signal peptide whereas residues 19-387 and 388-625 represents the heavy- and light- chains of the factor XIa molecule respectively. The protein forms five main distinct domains. Beginning from the N-terminus,each dimeric subunit contains 4 apple domains (<scene name='Sandbox/A1_domain/1'>A1</scene>, <scene name='Sandbox/A2_domain/1'>A2</scene>, <scene name='Sandbox/A3_domain/1'>A3</scene> and <scene name='Sandbox/A4_domain/2'>A4</scene>) which are characterized by approximately 90 or 91 amino acid residues. Protein-protein interactions are thought to be the primary role of the apple domains. The <scene name='Sandbox/A3_domain/1'>A3 domain</scene> is reported to mediate binding to platelet glycoprotein Ib (GPIb)<ref>PMID:15317813</ref> as well as interactions with exosite I of thrombin, and kringle 2 domain of prothrombin. The <scene name='Sandbox/A1_domain/1'>A1 domain</scene> is the main site of factor XI protein-protein interaction when in complex with high molecular weight kininogen<ref>PMID:7686159</ref>. The C-terminus (heavy chain) of factor XIa contain a trypsin-like catalytic domain <ref>PMID:893417</ref>. 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 found in hepatocyte growth factor and plasminogen <ref>PMID:10561497</ref>.  

Amino acid substitutions such as Phe283Leu<ref>PMID:17257616</ref> and Gly350Glu<ref>PMID:15026311 </ref> in the heavy chain results in an increased dimer dissociation and absence of dimer formation respectively. Some mutations in the factor XI A4 domain and catalytic domains are inherited as autosomal recessive bleeding diathesis however, other amino acid substitutions are exert a dominant negative effect on the normal monomer subunit affecting protein secretion. Studies suggest that dimerization is not affected under dominant negative mutations but the mutant subunit traps the normal subunit in the cell preventing its secretion. Majority of these missense mutations:Ser225Phe, Cys398Tyr, Gly400Val and Trp569Ser which produce a dominant negative effect involves residues found in the catalytic domain<ref>PMID:15026311 </ref>.

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==References==

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