Factor XIa: Difference between revisions
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[[Image:Coag_cartoon.jpg | thumb |350px| Schematic representation of the coagulation response]] | [[Image:Coag_cartoon.jpg | thumb |350px| Schematic representation of the coagulation response]] | ||
==Coagulation Factor XIa== | ==Coagulation Factor XIa== | ||
==Introduction== | ===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 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. | 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 factor IX to produce the serine protease factor IXa. | ||
<Structure load='2f83' size='350' frame='true' align='right' caption=' Crystal structure of factor XI' /> | |||
==Protein Structure== | ==Protein Structure== | ||
Factor XIa is disulfide linked-dimer of similar amino acid composition of approximately | 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. The C-terminus 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>. | ||
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 | 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). | ||
===β-turn=== | ===β-turn=== | ||
| Line 16: | Line 18: | ||
=== Factor FXIa dimer=== | === Factor FXIa dimer=== | ||
The β-sheets form a tight packing against each other with two A4 domains forming a large interface between the dimer subunits. Found in the central position is main interchain disulfide bond contributed Cys-321 | The β-sheets form a tight packing against each other with two A4 domains forming a large interface between the dimer subunits. Found in the central position is the main interchain disulfide bond contributed by Cys-321 located on the finger-like loop of the A4 domain. The apple domains form a V-shape in which two A2 domains are distanced ~50Å apart whiles the A1 and A3 domains from adjacent monomers are in close proximity of 5Å apart <ref>PMID:16699514</ref>. The <scene name='Sandbox/Hydrophobic_core/1'>hydrophobic core</scene> interface made up of Leu-284, Ile-290 and Tyr-329 and the <scene name='Sandbox/Salt_bridge/1'>salt bridge</scene> between Lys-331 of one monomer and Glu-287 of the other monomer are absolutely required for dimer formation<ref>PMID:11092900</ref>. Most of the complex protein-protein interactions involving factor XIa are mediated by the apple domains of the dimeric subunits. | ||
===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. | 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== | ||
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. Thrombin-catalyzed proteolysis of factor XI involves crucial interations with Glu-66, Lys-83 and Gln-84 of the A1 domain(this ensures maximum proximity to the activation loop of factor XI)of the factor XI molecule through its exosites I and II regions <ref>PMID:16699514</ref>. Thus binding of thrombin to one subunit of the zymogen dimer promotes cleavage of the bond between Arg369-Ile370 contained in the activation loop of factor XI. The activation loop (residues | 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. Thrombin-catalyzed proteolysis of factor XI involves crucial interations with Glu-66, Lys-83 and Gln-84 of the A1 domain (this ensures maximum proximity to the <scene name='Sandbox/Activation_loop/1'>activation loop</scene> of factor XI) of the factor XI molecule through its exosites I and II regions <ref>PMID:16699514</ref>. Thus binding of thrombin to one subunit of the zymogen dimer promotes cleavage of the bond between <scene name='Sandbox/Arg369-ile370/1'> Arg369-Ile370</scene> contained in the <scene name='Sandbox/Activation_loop/1'>activation loop</scene> of factor XI. The <scene name='Sandbox/Activation_loop/1'>activation loop</scene> (residues 370-376) consequently undergoes the greatest conformational change as Ile-370 is displaced ~20Å from its position in factor XI and inserts into the activation pocket of factor XIa producing the oxyanion hole in the active site of the protease <ref>PMID:14523451</ref>. | ||
==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/ | <Structure load='3bg8' size='350' frame='true' align='right' caption='Factor XIa light chain'/> | ||
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>. | |||
==Substrate Recognition and Cleavage== | ==Substrate Recognition and Cleavage== | ||
The primary substrate of factor XIa is another zymogen, factor IX which is cleavage sequentially at the peptides bonds between Arg145-Ala146 and Arg180-Val181 of factor IX to release an activation peptide <ref>PMID:17676929</ref>. Recognition of the substrate (factor IX) involves residues different from the active site residues. In the inactive zymogen (factor XI), the highly conserved Arg-184 is buried in the interface between the apple domains and the catalytic domain where it interacts with three residues: Ser-268 from the A3 domain and Asp-488 and Asn-566 in the catalytic domain. Thus following activation, Arg-184 is believed to constitute a switch which undegoes a conformational change breaking its interaction with Ser-268, Asp-488 and Asn 566 facilitating the protease interaction with factor IX <ref>PMID:16699514</ref>. . | The primary substrate of factor XIa is another zymogen, factor IX which is cleavage sequentially at the peptides bonds between Arg145-Ala146 and Arg180-Val181 of factor IX to release an activation peptide <ref>PMID:17676929</ref>. Recognition of the substrate (factor IX) involves residues different from the <scene name='Sandbox/Active_site/2'>active site</scene> residues. In the inactive zymogen (factor XI), the highly conserved <scene name='Sandbox/Arg_184/1'>Arg-184</scene> is buried in the interface between the apple domains and the catalytic domain where it interacts with <scene name='Sandbox/3_residues/1'>three residues</scene>: Ser-268 from the A3 domain and Asp-488 and Asn-566 in the catalytic domain. Thus following activation, <scene name='Sandbox/Arg_184/1'>Arg-184</scene> is believed to constitute a switch which undegoes a conformational change breaking its interaction with Ser-268, Asp-488 and Asn 566 facilitating the protease interaction with factor IX <ref>PMID:16699514</ref>. | ||
==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 | |||
. | |||
==References== | ==References== | ||
<references /> | <references /> | ||
Revision as of 01:53, 20 April 2011
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)[1]. 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 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
Factor XIa is a 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. The C-terminus contain a trypsin-like catalytic domain [2]. 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 [3].
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)[4]. 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).
β-turnβ-turn
This a beta turn in factor XIa
Helix Capping MotifHelix Capping Motif
Factor FXIa dimerFactor FXIa dimer
The β-sheets form a tight packing against each other with two A4 domains forming a large interface between the dimer subunits. Found in the central position is the main interchain disulfide bond contributed by Cys-321 located on the finger-like loop of the A4 domain. The apple domains form a V-shape in which two A2 domains are distanced ~50Å apart whiles the A1 and A3 domains from adjacent monomers are in close proximity of 5Å apart [5]. The interface made up of Leu-284, Ile-290 and Tyr-329 and the between Lys-331 of one monomer and Glu-287 of the other monomer are absolutely required for dimer formation[6]. Most of the complex protein-protein interactions involving factor XIa are mediated by the apple domains of the dimeric subunits.
Posttranslational ModificationPosttranslational Modification
Unlike most serine proteases which contain aγ-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 : 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 [7]. Ser-17 and Thr-22 are phosphorylated [8] whereas 5 N-linked glycosylations (GlcNAc) sites were also reported following glycoproteome analysis [9].
Formation of Factor XIaFormation of Factor XIa
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. Thrombin-catalyzed proteolysis of factor XI involves crucial interations with Glu-66, Lys-83 and Gln-84 of the A1 domain (this ensures maximum proximity to the of factor XI) of the factor XI molecule through its exosites I and II regions [10]. Thus binding of thrombin to one subunit of the zymogen dimer promotes cleavage of the bond between contained in the of factor XI. The (residues 370-376) consequently undergoes the greatest conformational change as Ile-370 is displaced ~20Å from its position in factor XI and inserts into the activation pocket of factor XIa producing the oxyanion hole in the active site of the protease [11].
Active Site ResiduesActive Site Residues
|
Similar to other serine proteases, the catalytic triad residues Ser-557, Asp-462 and His-413 constitute the of factor XIa. A 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 [12].
Substrate Recognition and CleavageSubstrate Recognition and Cleavage
The primary substrate of factor XIa is another zymogen, factor IX which is cleavage sequentially at the peptides bonds between Arg145-Ala146 and Arg180-Val181 of factor IX to release an activation peptide [13]. Recognition of the substrate (factor IX) involves residues different from the residues. In the inactive zymogen (factor XI), the highly conserved is buried in the interface between the apple domains and the catalytic domain where it interacts with : Ser-268 from the A3 domain and Asp-488 and Asn-566 in the catalytic domain. Thus following activation, is believed to constitute a switch which undegoes a conformational change breaking its interaction with Ser-268, Asp-488 and Asn 566 facilitating the protease interaction with factor IX [14].
Factor XIa DeficiencyFactor 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 [15]. Studies of the structural features of factor XI/FXIa has hightened in recent times due its implication .
ReferencesReferences
- ↑ Thompson RE, Mandle R Jr, Kaplan AP. Association of factor XI and high molecular weight kininogen in human plasma. J Clin Invest. 1977 Dec;60(6):1376-80. PMID:915004 doi:http://dx.doi.org/10.1172/JCI108898
- ↑ Bouma BN, Griffin JH. Human blood coagulation factor XI. Purification, properties, and mechanism of activation by activated factor XII. J Biol Chem. 1977 Sep 25;252(18):6432-7. PMID:893417
- ↑ Tordai H, Banyai L, Patthy L. The PAN module: the N-terminal domains of plasminogen and hepatocyte growth factor are homologous with the apple domains of the prekallikrein family and with a novel domain found in numerous nematode proteins. FEBS Lett. 1999 Nov 12;461(1-2):63-7. PMID:10561497
- ↑ Tordai H, Banyai L, Patthy L. The PAN module: the N-terminal domains of plasminogen and hepatocyte growth factor are homologous with the apple domains of the prekallikrein family and with a novel domain found in numerous nematode proteins. FEBS Lett. 1999 Nov 12;461(1-2):63-7. PMID:10561497
- ↑ Papagrigoriou E, McEwan PA, Walsh PN, Emsley J. Crystal structure of the factor XI zymogen reveals a pathway for transactivation. Nat Struct Mol Biol. 2006 Jun;13(6):557-8. Epub 2006 May 14. PMID:16699514 doi:10.1038/nsmb1095
- ↑ Dorfman R, Walsh PN. Noncovalent interactions of the Apple 4 domain that mediate coagulation factor XI homodimerization. J Biol Chem. 2001 Mar 2;276(9):6429-38. Epub 2000 Nov 22. PMID:11092900 doi:10.1074/jbc.M010340200
- ↑ McMullen BA, Fujikawa K, Davie EW. Location of the disulfide bonds in human coagulation factor XI: the presence of tandem apple domains. Biochemistry. 1991 Feb 26;30(8):2056-60. PMID:1998667
- ↑ Imami K, Sugiyama N, Kyono Y, Tomita M, Ishihama Y. Automated phosphoproteome analysis for cultured cancer cells by two-dimensional nanoLC-MS using a calcined titania/C18 biphasic column. Anal Sci. 2008 Jan;24(1):161-6. PMID:18187866
- ↑ Chen R, Jiang X, Sun D, Han G, Wang F, Ye M, Wang L, Zou H. Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry. J Proteome Res. 2009 Feb;8(2):651-61. PMID:19159218 doi:10.1021/pr8008012
- ↑ Papagrigoriou E, McEwan PA, Walsh PN, Emsley J. Crystal structure of the factor XI zymogen reveals a pathway for transactivation. Nat Struct Mol Biol. 2006 Jun;13(6):557-8. Epub 2006 May 14. PMID:16699514 doi:10.1038/nsmb1095
- ↑ Friedrich R, Panizzi P, Fuentes-Prior P, Richter K, Verhamme I, Anderson PJ, Kawabata S, Huber R, Bode W, Bock PE. Staphylocoagulase is a prototype for the mechanism of cofactor-induced zymogen activation. Nature. 2003 Oct 2;425(6957):535-9. PMID:14523451 doi:10.1038/nature01962
- ↑ Friedrich R, Panizzi P, Fuentes-Prior P, Richter K, Verhamme I, Anderson PJ, Kawabata S, Huber R, Bode W, Bock PE. Staphylocoagulase is a prototype for the mechanism of cofactor-induced zymogen activation. Nature. 2003 Oct 2;425(6957):535-9. PMID:14523451 doi:10.1038/nature01962
- ↑ Sinha D, Marcinkiewicz M, Navaneetham D, Walsh PN. Macromolecular substrate-binding exosites on both the heavy and light chains of factor XIa mediate the formation of the Michaelis complex required for factor IX-activation. Biochemistry. 2007 Aug 28;46(34):9830-9. Epub 2007 Aug 4. PMID:17676929 doi:10.1021/bi062296c
- ↑ Papagrigoriou E, McEwan PA, Walsh PN, Emsley J. Crystal structure of the factor XI zymogen reveals a pathway for transactivation. Nat Struct Mol Biol. 2006 Jun;13(6):557-8. Epub 2006 May 14. PMID:16699514 doi:10.1038/nsmb1095
- ↑ Saito H, Ratnoff OD, Bouma BN, Seligsohn U. Failure to detect variant (CRM+) plasma thromboplastin antecedent (factor XI) molecules in hereditary plasma thromboplastin antecedent deficiency: a study of 125 patients of several ethnic backgrounds. J Lab Clin Med. 1985 Dec;106(6):718-22. PMID:4067382