Factor XIa: Difference between revisions
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In contrast to a dysfunctional protein often reported in patients with defects in the vitamin K-dependent proteases, most cases of factor XIa deficiency are associated with low circulating amounts of the protein in the plasma <ref>PMID:4067382</ref>. Factor XI deficiency is a rare autosomal recessive [http://en.wikipedia.org/wiki/autosomal_recessive] disorder with a prevalence rate of about 1% in human populations. Individuals with the disease experience slight to mild bleeding diathesis which moderately increase during a surgical challenge. Studies of the structural features of factor XI/FXIa has hightened in recent times due its implication both venous<ref>10706899</ref> and arterial<ref>PMID:15733058</ref> thrombosis, pathology of sepsis and ischemia-reperfusion damage in the central nervous system. Mutations in the A4 domain of factor XIa often interfere with the ability of the protein to dimerize. | In contrast to a dysfunctional protein often reported in patients with defects in the vitamin K-dependent proteases, most cases of factor XIa deficiency are associated with low circulating amounts of the protein in the plasma <ref>PMID:4067382</ref>. Factor XI deficiency is a rare autosomal recessive [http://en.wikipedia.org/wiki/autosomal_recessive] disorder with a prevalence rate of about 1% in human populations. Individuals with the disease experience slight to mild bleeding diathesis which moderately increase during a surgical challenge. Studies of the structural features of factor XI/FXIa has hightened in recent times due its implication both venous<ref>10706899</ref> and arterial<ref>PMID:15733058</ref> thrombosis, pathology of sepsis and ischemia-reperfusion damage in the central nervous system. Mutations in the A4 domain of factor XIa often interfere with the ability of the protein to dimerize. | ||
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>. | 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>. | ||
==3D structures of Factor XI== | |||
===Factor XI=== | |||
[[2j8j]], [[2j8l]] – hFXIa A4 domain – human – NMR<br /> | |||
[[2f83]] - hFXI zymogen | |||
===Factor XI inhibitor complex=== | |||
3bg8 – hFXIa + clavatadine | |||
1zom, 1zsj, 1zsk, 1zlr, 1zmj, 1zml, 1zmn, 1zpz, 1zrk, 1ztj, 1ztk, 1ztl, 1zpb, 1zpc, 2fda, 1zsl, 1zhm, 1zhp, 1zhr - hFXI catalytic domain (mutant) + inhibitor | |||
1zjd - hFXI catalytic domain (mutant) + Kunitz protease inhibitory domain | |||
1xx9 - hFXI catalytic domain + ecotin (mutant) | |||
1xxd, 1xxf - hFXI catalytic domain (mutant) + ecotin (mutant) | |||
==References== | ==References== | ||
<references /> | <references /> | ||