Faktor XI

F11
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	1XX9, 1XXD, 1XXF, 1ZHM, 1ZHP, 1ZHR, 1ZJD, 1ZLR, 1ZMJ, 1ZML, 1ZMN, 1ZOM, 1ZPB, 1ZPC, 1ZPZ, 1ZRK, 1ZSJ, 1ZSK, 1ZSL, 1ZTJ, 1ZTK, 1ZTL, 2F83, 2FDA, 2J8J, 2J8L, 3BG8, 3SOR, 3SOS, 4CR5, 4CR9, 4CRA, 4CRB, 4CRC, 4CRD, 4CRE, 4CRF, 4CRG, 4NA7, 4NA8, 4TY6, 4TY7, 4WXI, 4X6M, 4X6N, 4X6O, 4X6P, 4Y8X, 4Y8Y, 4Y8Z, 4D7F, 5E2O, 5E2P, 4D76, 4D7G, 5EXL, 5I25, 5EXM, 5EOD, 5EXN, 5EOK
Identifikatori
Aliasi	F11
Vanjski ID-jevi	OMIM: 264900 MGI: 99481 HomoloGene: 86654 GeneCards: F11
Lokacija gena (čovjek)
Hrom.	Hromosom 4 (čovjek)
Kraj	186,289,681 bp
Lokacija gena (miš)
Hrom.	Hromosom 8 (miš)
Kraj	45,715,068 bp
Obrazac RNK ekspresije
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• serine-type aminopeptidase activity; • GO:0070122 peptidase activity; • heparin binding; • serine-type endopeptidase activity; • serine-type peptidase activity; • GO:0001948, GO:0016582 vezivanje za proteine; • hydrolase activity; • vezivanje identičnih proteina;
Ćelijska komponenta	• extracellular region; • ćelijska membrana; • Egzosom; • membrana; • Vanćelijsko;
Biološki proces	• Hemostaza; • blood coagulation, intrinsic pathway; • plasminogen activation; • regulation of blood coagulation; • Proteoliza; • positive regulation of fibrinolysis; • Koagulacija (krv);
	Izvori:Amigo / QuickGO
Ortolozi
	2160
	109821
	ENSG00000088926
	ENSMUSG00000031645
	P03951
	Q91Y47
	NM_000128; NM_019559; NM_001354804
	NM_028066
	NP_000119; NP_001341733
	NP_082342
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Faktor XI ili plazmatski tromboplastinski prethodnik jest protein koji je kod ljudi kodiran genom F11 sa hromosoma 4. To je zimogeni oblik faktora XIa, jedan od enzima u koagulacijskoj kaskadi. Kao i mnogi drugi faktori koagulacije, to je serin-proteaza.^[5]^[6]^[7]^[8]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 625 aminokiselina, а molekulska težina 70 109 Da.^[9]

C: Cistein

D: Asparaginska kiselina

E: Glutaminska kiselina

F: Fenilalanin

G: Glicin

H: Histidin

I: Izoleucin

K: Lizin

L: Leucin

M: Metionin

N: Asparagin

P: Prolin

Q: Glutamin

R: Arginin

S: Serin

T: Treonin

V: Valin

W: Triptofan

Y: Tirozin

10	20	30	40	50
MIFLYQVVHF	ILFTSVSGEC	VTQLLKDTCF	EGGDITTVFT	PSAKYCQVVC
TYHPRCLLFT	FTAESPSEDP	TRWFTCVLKD	SVTETLPRVN	RTAAISGYSF
KQCSHQISAC	NKDIYVDLDM	KGINYNSSVA	KSAQECQERC	TDDVHCHFFT
YATRQFPSLE	HRNICLLKHT	QTGTPTRITK	LDKVVSGFSL	KSCALSNLAC
IRDIFPNTVF	ADSNIDSVMA	PDAFVCGRIC	THHPGCLFFT	FFSQEWPKES
QRNLCLLKTS	ESGLPSTRIK	KSKALSGFSL	QSCRHSIPVF	CHSSFYHDTD
FLGEELDIVA	AKSHEACQKL	CTNAVRCQFF	TYTPAQASCN	EGKGKCYLKL
SSNGSPTKIL	HGRGGISGYT	LRLCKMDNEC	TTKIKPRIVG	GTASVRGEWP
WQVTLHTTSP	TQRHLCGGSI	IGNQWILTAA	HCFYGVESPK	ILRVYSGILN
QSEIKEDTSF	FGVQEIIIHD	QYKMAESGYD	IALLKLETTV	NYTDSQRPIC
LPSKGDRNVI	YTDCWVTGWG	YRKLRDKIQN	TLQKAKIPLV	TNEECQKRYR
GHKITHKMIC	AGYREGGKDA	CKGDSGGPLS	CKHNEVWHLV	GITSWGEGCA
QRERPGVYTN	VVEYVDWILE	KTQAV

Struktura

Iako je sintetiziran kao jedan polipeptidni lanac, FXI cirkulira kao homodimer. Svaki lanac ima relativnu molekulsku masu od približno 80.000. Tipske koncentracije FXI u plazmi su 5 μg/mL, što odgovara koncentraciji dimera FXI u plazmi od približno 30 nM. Na hromosomu 4, gen FXI je dug 23 kb, ima 15 egzona u regiji 4q32-35.^[6]^[7]

Faktor XI se sastoji od četiri PAN-domena, koji stvaraju platformu nalik na disk oko baze 5., domena katalitske serin-proteaze. Jedan sadrži mjesto vezanja za trombin, drugi za kininogen visoke molekulske težine, treći za faktor IX, heparin i glikoprotein Ib, a četvrti je uključen u formiranje homodimera faktora XI, uključujući cisteinski ostatak koji stvara disulfidnu vezu.

U homodimeru, domeni PAN stvaraju dvije diskoidne platforme, povezane zajedno pod uglom, pri čemu katalitski domeni strše sa svake strane dimera.

Aktivacija trombinom ili faktorom XIIa se postiže cijepanjem Arg369-Ile370 peptidnih veza na obje podjedinice dimera. Ovo rezultira djelimičnim odvajanjem katalitskog domena od diskolikih domena PAN, još uvijek vezanih za četvrti domen disulfidnom vezom, ali sada dalje od trećeg domena.

Smatra se da ovo otkriva mjesto vezanja faktora IX trećeg PAN domena, omogućavajući proteazno delovanje faktora XI na njemu.^[10]

Funkcija

Faktor XI (FXI) proizvodi jetra i cirkulira kao homodimer u svom neaktivnom obliku.^[11] Poluvrijeme eliminacije FXI u plazmi je približno 52 sata. Zimogeni faktor aktivira se u faktor XIa, pomoću faktora XIIa (FXIIa), trombina i samog FXIa; zbog svoje aktivacije pomoću FXIIa, FXI je član "kontaktnog puta" (koji uključuje HMWK, prekalikrein, faktor XII, faktor XI i faktor IX).^[12]

Faktor XIa aktivira faktor IX selektivnim cijepanjem arg-ala i arg-val peptidne veze . Faktor IXa, zauzvrat, formira kompleks sa faktorom VIIIa (FIXa-FVIIIa) i aktivira faktor X.

Inhibitori faktora XIa uključuju protein Z-ovisni inhibitor proteaze (ZPI, član inhibitor serin proteaze/serpin klase proteina), koji je nezavisan od proteina Z (njegovo djelovanje na faktor X, međutim, zavisi od proteina Z, otuda i njegovo ime).

Klinički značaj

Nedostatak faktora XI uzrokuje rijetku hemofiliju C; ovo se uglavnom dešava kod Aškenazi Jevreja i vjeruje se da pogađa otprilike 8% te populacije. ]]Rjeđe, hemofilija C može se naći kod Jevreja iračkog porijekla i kod izraelskih Arapa. Stanje je opisano u drugim populacijama u oko 1% slučajeva. To je autosomno recesivni poremećaj. Spontanog krvarenja je malo, ali hirurški zahvati mogu uzrokovati prekomjeran gubitak krvi i potrebna je profilaksa.^[13]

Nizak nivo faktora XI se takođe javlja u mnogim drugim bolesnim stanjima, uključujući Noonanov sindrom.

Visoki nivoi faktora XI su uključeni u trombozu, iako je neizvjesno šta određuje ove nivoe i koliko je ozbiljno prokoagulantno stanje.

Također pogledajte

Put kontaktne aktivacije
Put tkivnog faktora (također poznat i kao vanjski put)

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000088926 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000031645 - Ensembl, maj 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Šablon:EVC.PNGcite journal
^ ^a ^b Asakai R, Davie EW, Chung DW (Nov 1987). "Organization of the gene for human factor XI". Biochemistry. 26 (23): 7221–8. doi:10.1021/bi00397a004. PMID 2827746.
^ ^a ^b Kato A, Asakai R, Davie EW, Aoki N (1989). "Factor XI gene (F11) is located on the distal end of the long arm of human chromosome 4". Cytogenetics and Cell Genetics. 52 (1–2): 77–8. doi:10.1159/000132844. PMID 2612218.
^ Buetow KH, Shiang R, Yang P, Nakamura Y, Lathrop GM, White R, Wasmuth JJ, Wood S, Berdahl LD, Leysens NJ (maj 1991). "A detailed multipoint map of human chromosome 4 provides evidence for linkage heterogeneity and position-specific recombination rates". American Journal of Human Genetics. 48 (5): 911–25. PMC 1683054. PMID 1673289.
^ "UniProt, P03951" (jezik: engleski). Pristupljeno 26. 10. 2021.
^ Emsley J, McEwan PA, Gailani D (Apr 2010). "Structure and function of factor XI". Blood. 115 (13): 2569–77. doi:10.1182/blood-2009-09-199182. PMC 4828079. PMID 20110423.
^ Wu W, Sinha D, Shikov S, Yip CK, Walz T, Billings PC, Lear JD, Walsh PN (Jul 2008). "Factor XI homodimer structure is essential for normal proteolytic activation by factor XIIa, thrombin, and factor XIa". The Journal of Biological Chemistry. 283 (27): 18655–64. doi:10.1074/jbc.M802275200. PMC 2441546. PMID 18441012.
^ Walsh PN (Jul 2001). "Roles of platelets and factor XI in the initiation of blood coagulation by thrombin". Thrombosis and Haemostasis. 86 (1): 75–82. doi:10.1055/s-0037-1616203. PMID 11487044. Arhivirano s originala, 16. 4. 2016. Pristupljeno 7. 1. 2009.
^ Bolton-Maggs PH (Jun 1996). "Factor XI deficiency". Baillière's Clinical Haematology. 9 (2): 355–68. doi:10.1016/S0950-3536(96)80068-0. PMID 8800510.

Dopunska literatura

Gailani D, Zivelin A, Sinha D, Walsh PN (2005). "Do platelets synthesize factor XI?". Journal of Thrombosis and Haemostasis. 2 (10): 1709–12. doi:10.1111/j.1538-7836.2004.00935.x. PMID 15456479. S2CID 5962587.
Dossenbach-Glaninger A, Hopmeier P (Jun 2005). "Coagulation factor XI: a database of mutations and polymorphisms associated with factor XI deficiency". Blood Coagulation & Fibrinolysis. 16 (4): 231–8. doi:10.1097/01.mbc.0000169214.62560.a5. PMID 15870541. S2CID 23922781.
Seligsohn U (Jul 2007). "Factor XI in haemostasis and thrombosis: past, present and future". Thrombosis and Haemostasis. 98 (1): 84–9. doi:10.1160/th07-04-0246. PMID 17597996.
Meijers JC, Davie EW, Chung DW (Mar 1992). "Expression of human blood coagulation factor XI: characterization of the defect in factor XI type III deficiency". Blood. 79 (6): 1435–40. doi:10.1182/blood.V79.6.1435.1435. PMID 1547342.
Gailani D, Broze GJ (Aug 1991). "Factor XI activation in a revised model of blood coagulation". Science. 253 (5022): 909–12. Bibcode:1991Sci...253..909G. doi:10.1126/science.1652157. PMID 1652157. S2CID 9262836.
Buetow KH, Shiang R, Yang P, Nakamura Y, Lathrop GM, White R, Wasmuth JJ, Wood S, Berdahl LD, Leysens NJ (maj 1991). "A detailed multipoint map of human chromosome 4 provides evidence for linkage heterogeneity and position-specific recombination rates". American Journal of Human Genetics. 48 (5): 911–25. PMC 1683054. PMID 1673289.
Bodfish P, Warne D, Watkins C, Nyberg K, Spurr NK (1992). "Dinucleotide repeat polymorphism in the human coagulation factor XI gene, intron B (F11), detected using the polymerase chain reaction". Nucleic Acids Research. 19 (24): 6979. doi:10.1093/nar/19.24.6979-a. PMC 329377. PMID 1762944.
Clarkson K, Rosenfeld B, Fair J, Klein A, Bell W (Dec 1991). "Factor XI deficiency acquired by liver transplantation". Annals of Internal Medicine. 115 (11): 877–9. doi:10.7326/0003-4819-115-11-877. PMID 1952475.
McMullen BA, Fujikawa K, Davie EW (Feb 1991). "Location of the disulfide bonds in human coagulation factor XI: the presence of tandem apple domains". Biochemistry. 30 (8): 2056–60. doi:10.1021/bi00222a008. PMID 1998667.
Naito K, Fujikawa K (Apr 1991). "Activation of human blood coagulation factor XI independent of factor XII. Factor XI is activated by thrombin and factor XIa in the presence of negatively charged surfaces". The Journal of Biological Chemistry. 266 (12): 7353–8. doi:10.1016/S0021-9258(20)89453-8. PMID 2019570.
Asakai R, Chung DW, Davie EW, Seligsohn U (Jul 1991). "Factor XI deficiency in Ashkenazi Jews in Israel". The New England Journal of Medicine. 325 (3): 153–8. doi:10.1056/NEJM199107183250303. PMID 2052060.
España F, Berrettini M, Griffin JH (Aug 1989). "Purification and characterization of plasma protein C inhibitor". Thrombosis Research. 55 (3): 369–84. doi:10.1016/0049-3848(89)90069-8. PMID 2551064.
Asakai R, Chung DW, Ratnoff OD, Davie EW (Oct 1989). "Factor XI (plasma thromboplastin antecedent) deficiency in Ashkenazi Jews is a bleeding disorder that can result from three types of point mutations". Proceedings of the National Academy of Sciences of the United States of America. 86 (20): 7667–71. Bibcode:1989PNAS...86.7667A. doi:10.1073/pnas.86.20.7667. PMC 298131. PMID 2813350.
Asakai R, Davie EW, Chung DW (1988). "Organization of the gene for human factor XI". Biochemistry. 26 (23): 7221–8. doi:10.1021/bi00397a004. PMID 2827746.
Fujikawa K, Chung DW, Hendrickson LE, Davie EW (maj 1986). "Amino acid sequence of human factor XI, a blood coagulation factor with four tandem repeats that are highly homologous with plasma prekallikrein". Biochemistry. 25 (9): 2417–24. doi:10.1021/bi00357a018. PMID 3636155.
Warn-Cramer BJ, Bajaj SP (1986). "Stoichiometry of binding of high molecular weight kininogen to factor XI/XIa". Biochemical and Biophysical Research Communications. 133 (2): 417–22. doi:10.1016/0006-291X(85)90922-2. PMID 3936495.
Bouma BN, Vlooswijk RA, Griffin JH (Nov 1983). "Immunologic studies of human coagulation factor XI and its complex with high molecular weight kininogen". Blood. 62 (5): 1123–31. doi:10.1182/blood.V62.5.1123.1123. PMID 6626744.
Tuszynski GP, Bevacqua SJ, Schmaier AH, Colman RW, Walsh PN (Jun 1982). "Factor XI antigen and activity in human platelets". Blood. 59 (6): 1148–56. doi:10.1182/blood.V59.6.1148.1148. PMID 7044446.
Imanaka Y, Lal K, Nishimura T, Bolton-Maggs PH, Tuddenham EG, McVey JH (Aug 1995). "Identification of two novel mutations in non-Jewish factor XI deficiency". British Journal of Haematology. 90 (4): 916–20. doi:10.1111/j.1365-2141.1995.tb05215.x. PMID 7669672. S2CID 21900907.
Pugh RE, McVey JH, Tuddenham EG, Hancock JF (Mar 1995). "Six point mutations that cause factor XI deficiency". Blood. 85 (6): 1509–16. doi:10.1182/blood.V85.6.1509.bloodjournal8561509. PMID 7888672.
Riley PW, Cheng H, Samuel D, Roder H, Walsh PN (Mar 2007). "Dimer dissociation and unfolding mechanism of coagulation factor XI apple 4 domain: spectroscopic and mutational analysis". Journal of Molecular Biology. 367 (2): 558–73. doi:10.1016/j.jmb.2006.12.066. PMC 1945241. PMID 17257616.
Samuel D, Cheng H, Riley PW, Canutescu AA, Nagaswami C, Weisel JW, Bu Z, Walsh PN, Roder H (Oct 2007). "Solution structure of the A4 domain of factor XI sheds light on the mechanism of zymogen activation". Proceedings of the National Academy of Sciences of the United States of America. 104 (40): 15693–8. Bibcode:2007PNAS..10415693S. doi:10.1073/pnas.0703080104. PMC 1987390. PMID 17884987.

Vanjski linkovi

The MEROPS online database for peptidases and their inhibitors: S01.213 Arhivirano 29. 5. 2020. na Wayback Machine

Portal Biologija

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000088926 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000031645 - Ensembl, maj 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid3636155-5] Šablon:EVC.PNGcite journal

[pmid2827746-6] Asakai R, Davie EW, Chung DW (Nov 1987). "Organization of the gene for human factor XI". Biochemistry. 26 (23): 7221–8. doi:10.1021/bi00397a004. PMID 2827746.

[pmid2612218-7] Kato A, Asakai R, Davie EW, Aoki N (1989). "Factor XI gene (F11) is located on the distal end of the long arm of human chromosome 4". Cytogenetics and Cell Genetics. 52 (1–2): 77–8. doi:10.1159/000132844. PMID 2612218.

[pmid1673289-8] Buetow KH, Shiang R, Yang P, Nakamura Y, Lathrop GM, White R, Wasmuth JJ, Wood S, Berdahl LD, Leysens NJ (maj 1991). "A detailed multipoint map of human chromosome 4 provides evidence for linkage heterogeneity and position-specific recombination rates". American Journal of Human Genetics. 48 (5): 911–25. PMC 1683054. PMID 1673289.

[UniProt-9] "UniProt, P03951" (jezik: engleski). Pristupljeno 26. 10. 2021.

[10] Emsley J, McEwan PA, Gailani D (Apr 2010). "Structure and function of factor XI". Blood. 115 (13): 2569–77. doi:10.1182/blood-2009-09-199182. PMC 4828079. PMID 20110423.

[pmid18441012-11] Wu W, Sinha D, Shikov S, Yip CK, Walz T, Billings PC, Lear JD, Walsh PN (Jul 2008). "Factor XI homodimer structure is essential for normal proteolytic activation by factor XIIa, thrombin, and factor XIa". The Journal of Biological Chemistry. 283 (27): 18655–64. doi:10.1074/jbc.M802275200. PMC 2441546. PMID 18441012.

[pmid11487044-12] Walsh PN (Jul 2001). "Roles of platelets and factor XI in the initiation of blood coagulation by thrombin". Thrombosis and Haemostasis. 86 (1): 75–82. doi:10.1055/s-0037-1616203. PMID 11487044. Arhivirano s originala, 16. 4. 2016. Pristupljeno 7. 1. 2009.

[pmid8800510-13] Bolton-Maggs PH (Jun 1996). "Factor XI deficiency". Baillière's Clinical Haematology. 9 (2): 355–68. doi:10.1016/S0950-3536(96)80068-0. PMID 8800510.

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