Factor XIa: Difference between revisions
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==Protein Structure== | ==Protein Structure== | ||
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 (A1, A2, A3 and A4) 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 A3 domain 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 A1 domain 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 growtth factor and plasminogen <ref>PMID:10561497</ref>. | 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 growtth factor and plasminogen <ref>PMID:10561497</ref>. | ||
===''Secondary structure''=== | ===''Secondary structure''=== | ||
About 36 β-strands have been observed in the crystal structure of factor XI with twice as much found in the heavy chain (25 β-strands) compared to the light chain (11 β-strands). The topology of the apple domain reveals 7 antiparallel β-sheets and an α-helix which fold into a compact structure as oppose to an extended structure found in the vitamin K-dependent serine proteases. This core PAN topology is also found in leech antiplatelet protein and hepatocyte growth factor)<ref>PMID:10561497</ref>. A single disulfide linkage connects the C- and N-terminals of the dimer whereas two disulfide bond join the helix to the 4β- and 5β-sheets. The apple domains of factor XIa are tightly linked to each other forming a disk-like structure close to the base of the C-terminal catalytic domain. This observation is consistent with the high surface area 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). | About 36 β-strands have been observed in the crystal structure of factor XI with twice as much found in the heavy chain (25 β-strands) compared to the light chain (11 β-strands). The topology of the apple domain reveals 7 antiparallel β-sheets and an α-helix which fold into a compact structure as oppose to an extended structure found in the vitamin K-dependent serine proteases. This core PAN topology is also found in leech antiplatelet protein and hepatocyte growth factor)<ref>PMID:10561497</ref>. A single disulfide linkage connects the C- and N-terminals of the dimer whereas two disulfide bond join the helix to the 4β- and 5β-sheets. The apple domains of factor XIa are tightly linked to each other forming a disk-like structure close to the base of the C-terminal catalytic domain. This observation is consistent with the high surface area measurements for the side interfaces between apple domains <scene name='Sandbox/A1_domain/1'>A1</scene> and <scene name='Sandbox/A2_domain/1'>A2</scene> (441ÅxÅ) and between <scene name='Sandbox/A3_domain/1'>A3</scene> and <scene name='Sandbox/A4_domain/2'>A4</scene> (444ÅxÅ) in contrast to smaller end interfaces between <scene name='Sandbox/A1_domain/1'>A1</scene> and <scene name='Sandbox/A4_domain/2'>A4</scene> (380ÅxÅ) and between <scene name='Sandbox/A2_domain/1'>A2</scene> and <scene name='Sandbox/A3_domain/1'>A3</scene> (284ÅxÅ). | ||
'''β-turn''' | '''β-turn''' | ||
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===Posttranslational Modification=== | ===Posttranslational Modification=== | ||
Unlike most serine proteases which contain a[http://en.wikipedia.org/wiki/Gla_domain γ-carboxyglutamic acid (Gla)]domain, which facilitates the binding of vitamin-K dependent coagulation proteases to phospholipid vesicles, plasma factor XIa lacks the Gla domain. Meanwhile the protease undergoes considerable posttranslational retailing following it synthesis. Approximately <scene name='Sandbox/19_disulfide_bonds/1'>19 disulfide bonds</scene>: 15 of which are confirmed and 4 potential disulfide linkages are reported to be present in factor XIa molecule. The homodimers are linked by a single disulfide bond at Cys-321 connecting the A4 domains of each subunit <ref>PMID:1998667</ref>. Ser-17 and Thr-22 are phosphorylated <ref>PMID:18187866</ref> whereas 5 N-linked glycosylations (GlcNAc) sites were also reported following glycoproteome analysis <ref>PMID:19159218</ref>. | Unlike most serine proteases which contain a [http://en.wikipedia.org/wiki/Gla_domain γ-carboxyglutamic acid (Gla)] domain, which facilitates the binding of vitamin-K dependent coagulation proteases to phospholipid vesicles, plasma factor XIa lacks the Gla domain. Meanwhile the protease undergoes considerable posttranslational retailing following it synthesis. Approximately <scene name='Sandbox/19_disulfide_bonds/1'>19 disulfide bonds</scene>: 15 of which are confirmed and 4 potential disulfide linkages are reported to be present in factor XIa molecule. The homodimers are linked by a single disulfide bond at Cys-321 connecting the A4 domains of each subunit <ref>PMID:1998667</ref>. Ser-17 and Thr-22 are phosphorylated <ref>PMID:18187866</ref> whereas 5 N-linked glycosylations (GlcNAc) sites were also reported following glycoproteome analysis <ref>PMID:19159218</ref>. | ||
==Formation of Factor XIa== | ==Formation of Factor XIa== | ||
<Structure load='3bg8' size='350' frame='true' align='right' caption='Factor XIa light chain'/> | |||
Factor XI is partially proteolyzed ''in vitro'' by thrombin and factor XIIa generating the active serine-protease, factor XIa. Similar to other chymotrypsin-like proteases, its topology consist of two β-barrels linked through a central loop. Next to the C-terminal Cys-356 of the factor XI heavy chain, the polypeptide forms a 3-10 helix conformation and again turn sharply 90 degrees at Cys-362 forming a disulfide bond with Cys-482 within the active site region. | Factor XI is partially proteolyzed ''in vitro'' by thrombin and factor XIIa generating the active serine-protease, factor XIa. Similar to other chymotrypsin-like proteases, its topology consist of two β-barrels linked through a central loop. Next to the C-terminal Cys-356 of the factor XI heavy chain, the polypeptide forms a 3-10 helix conformation and again turn sharply 90 degrees at Cys-362 forming a disulfide bond with Cys-482 within the active site region. | ||
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==Active Site Residues== | ==Active Site Residues== | ||
Similar to other serine proteases, the [http://en.wikipedia.org/wiki/Catalytic_triad catalytic triad] residues Ser-557, Asp-462 and His-413 constitute the <scene name='Sandbox/Active_site/2'>active site</scene> of factor XIa. A [http://en.wikipedia.org/wiki/Low-barrier_hydrogen_bond low barrier hydrogen bond (LBHB)] formed between the carboxyl group of Asp-462 and imidazole nitrogen of His 413 causes the deprotonation Ser-557 (enhacing its nucleophilicity). Thus catalysis involves a nucleophilic attack by Ser-557 on the carbonyl carbon of the target amino acid at the C-terminal of the substrate producing an intermediate which is stablized by the oxyanion hole. Rearrangement of the resulting tetrahedral intermediate and a second nucleophilic attack by water yields a cleaved peptide with a free carboxyl end <ref>PMID:14523451</ref>. | Similar to other serine proteases, the [http://en.wikipedia.org/wiki/Catalytic_triad catalytic triad] residues Ser-557, Asp-462 and His-413 constitute the <scene name='Sandbox/Active_site/2'>active site</scene> of factor XIa. A [http://en.wikipedia.org/wiki/Low-barrier_hydrogen_bond low barrier hydrogen bond (LBHB)] formed between the carboxyl group of Asp-462 and imidazole nitrogen of His 413 causes the deprotonation Ser-557 (enhacing its nucleophilicity). Thus catalysis involves a nucleophilic attack by Ser-557 on the carbonyl carbon of the target amino acid at the C-terminal of the substrate producing an intermediate which is stablized by the oxyanion hole. Rearrangement of the resulting tetrahedral intermediate and a second nucleophilic attack by water yields a cleaved peptide with a free carboxyl end <ref>PMID:14523451</ref>. | ||
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==Evolutionary relationship== | ==Evolutionary relationship== | ||
{{STRUCTURE_2f83|PDB=2f83|SCENE=}} | |||
==Factor XIa Deficiency== | ==Factor XIa Deficiency== | ||
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>. 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 od 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 od 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>. | ||
==References== | ==References== | ||
<references /> | <references /> | ||