FA12_HUMAN
ID FA12_HUMAN Reviewed; 615 AA.
AC P00748; P78339;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 11-JAN-2011, sequence version 3.
DT 03-AUG-2022, entry version 243.
DE RecName: Full=Coagulation factor XII;
DE EC=3.4.21.38;
DE AltName: Full=Hageman factor;
DE Short=HAF;
DE Contains:
DE RecName: Full=Coagulation factor XIIa heavy chain;
DE Contains:
DE RecName: Full=Beta-factor XIIa part 1;
DE Contains:
DE RecName: Full=Coagulation factor XIIa light chain;
DE AltName: Full=Beta-factor XIIa part 2;
DE Flags: Precursor;
GN Name=F12;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT PRO-207.
RX PubMed=2888762; DOI=10.1016/s0021-9258(19)76478-3;
RA Cool D.E., McGillivray R.T.A.;
RT "Characterization of the human blood coagulation factor XII gene.
RT Intron/exon gene organization and analysis of the 5'-flanking region.";
RL J. Biol. Chem. 262:13662-13673(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS PRO-207; ASP-545 AND
RP HIS-605.
RG SeattleSNPs variation discovery resource;
RL Submitted (AUG-2002) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A.,
RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R.,
RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L.,
RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N.,
RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J.,
RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A.,
RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 4-615, AND VARIANT PRO-207.
RX PubMed=3754331; DOI=10.1093/nar/14.7.3146;
RA Tripodi M., Citarella F., Guida S., Galeffi P., Fantoni A., Cortese R.;
RT "cDNA sequence coding for human coagulation factor XII (Hageman).";
RL Nucleic Acids Res. 14:3146-3146(1986).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 14-615, AND VARIANT PRO-207.
RX PubMed=3877053; DOI=10.1016/s0021-9258(17)38776-8;
RA Cool D.E., Edgell C.-J.S., Louie G.V., Zoller M.J., Brayer G.D.,
RA McGillivray R.T.A.;
RT "Characterization of human blood coagulation factor XII cDNA. Prediction of
RT the primary structure of factor XII and the tertiary structure of beta-
RT factor XIIa.";
RL J. Biol. Chem. 260:13666-13676(1985).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 146-615, AND VARIANT PRO-207.
RX PubMed=3011063; DOI=10.1021/bi00355a009;
RA Que B.G., Davie E.W.;
RT "Characterization of a cDNA coding for human factor XII (Hageman factor).";
RL Biochemistry 25:1525-1528(1986).
RN [7]
RP PROTEIN SEQUENCE OF 20-379, GLYCOSYLATION AT ASN-249; THR-299; THR-305;
RP SER-308; THR-328; THR-329 AND THR-337, AND VARIANT PRO-207.
RX PubMed=3886654; DOI=10.1016/s0021-9258(18)89026-3;
RA McMullen B.A., Fujikawa K.;
RT "Amino acid sequence of the heavy chain of human alpha-factor XIIa
RT (activated Hageman factor).";
RL J. Biol. Chem. 260:5328-5341(1985).
RN [8]
RP PROTEIN SEQUENCE OF 354-362 AND 373-615.
RX PubMed=6604055; DOI=10.1016/s0021-9258(17)44364-x;
RA Fujikawa K., McMullen B.A.;
RT "Amino acid sequence of human beta-factor XIIa.";
RL J. Biol. Chem. 258:10924-10933(1983).
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 561-615, AND VARIANT FA12D ARG-589.
RC TISSUE=Blood;
RX PubMed=8528215; DOI=10.1093/hmg/4.7.1235;
RA Schloesser M., Hofferbert S., Bartz U., Lutze G., Lammle B., Engel W.;
RT "The novel acceptor splice site mutation 11396(G-->A) in the factor XII
RT gene causes a truncated transcript in cross-reacting material negative
RT patients.";
RL Hum. Mol. Genet. 4:1235-1237(1995).
RN [10]
RP GLYCOSYLATION AT THR-109.
RX PubMed=1544894; DOI=10.1016/s0021-9258(18)42736-6;
RA Harris R.J., Ling V.T., Spellman M.W.;
RT "O-linked fucose is present in the first epidermal growth factor domain of
RT factor XII but not protein C.";
RL J. Biol. Chem. 267:5102-5107(1992).
RN [11]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-433.
RC TISSUE=Plasma;
RX PubMed=14760718; DOI=10.1002/pmic.200300556;
RA Bunkenborg J., Pilch B.J., Podtelejnikov A.V., Wisniewski J.R.;
RT "Screening for N-glycosylated proteins by liquid chromatography mass
RT spectrometry.";
RL Proteomics 4:454-465(2004).
RN [12]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-249 AND ASN-433.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J.,
RA Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [13]
RP INVOLVEMENT IN FA12D.
RX PubMed=2882793;
RA Bernardi F., Marchetti G., Patracchini P., del Senno L., Tripodi M.,
RA Fantoni A., Bartolai S., Vannini F., Felloni L., Rossi L., Panicucci F.,
RA Conconi F.;
RT "Factor XII gene alteration in Hageman trait detected by TaqI restriction
RT enzyme.";
RL Blood 69:1421-1424(1987).
RN [14]
RP INTERACTION WITH HRG, AND FUNCTION.
RX PubMed=21304106; DOI=10.1182/blood-2010-07-290551;
RA Macquarrie J.L., Stafford A.R., Yau J.W., Leslie B.A., Vu T.T.,
RA Fredenburgh J.C., Weitz J.I.;
RT "Histidine-rich glycoprotein binds factor XIIa with high affinity and
RT inhibits contact-initiated coagulation.";
RL Blood 117:4134-4141(2011).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (1.62 ANGSTROMS) OF 133-213, AND DISULFIDE BONDS.
RX PubMed=23385745; DOI=10.1107/s1744309113000286;
RA Beringer D.X., Kroon-Batenburg L.M.;
RT "The structure of the FnI-EGF-like tandem domain of coagulation factor XII
RT solved using SIRAS.";
RL Acta Crystallogr. F 69:94-102(2013).
RN [17]
RP VARIANT FA12D SER-590.
RX PubMed=2510163; DOI=10.1073/pnas.86.21.8319;
RA Miyata T., Kawabata S., Iwanaga S., Takahashi I., Alving B., Saito H.;
RT "Coagulation factor XII (Hageman factor) Washington D.C.: inactive factor
RT XIIa results from Cys-571-->Ser substitution.";
RL Proc. Natl. Acad. Sci. U.S.A. 86:8319-8322(1989).
RN [18]
RP VARIANT FA12D PRO-372.
RX PubMed=8049433;
RA Hovinga J.K., Schaller J., Stricker H., Wuillemin W.A., Furlan M.,
RA Laemmle B.;
RT "Coagulation factor XII Locarno: the functional defect is caused by the
RT amino acid substitution Arg-353-->Pro leading to loss of a kallikrein
RT cleavage site.";
RL Blood 84:1173-1181(1994).
RN [19]
RP VARIANTS FA12D MET-414; GLN-417; ASN-461 AND ARG-589.
RX PubMed=9354665;
RA Schloesser M., Zeerleder S., Lutze G., Halbmayer W.-M., Hofferbert S.,
RA Hinney B., Koestering H., Laemmle B., Pindur G., Thies K., Koehler M.,
RA Engel W.;
RT "Mutations in the human factor XII gene.";
RL Blood 90:3967-3977(1997).
RN [20]
RP VARIANT FA12D CYS-53.
RX PubMed=10361128;
RA Kondo S., Tokunaga F., Kawano S., Oono Y., Kumagai S., Koide T.;
RT "Factor XII Tenri, a novel cross-reacting material negative factor XII
RT deficiency, occurs through a proteasome-mediated degradation.";
RL Blood 93:4300-4308(1999).
RN [21]
RP VARIANTS FA12D PRO-142 AND LYS-440, AND CHARACTERIZATION OF VARIANTS FA12D
RP PRO-142 AND LYS-440.
RX PubMed=11776307;
RA Kanaji T., Kanaji S., Osaki K., Kuroiwa M., Sakaguchi M., Mihara K.,
RA Niho Y., Okamura T.;
RT "Identification and characterization of two novel mutations (Q421K and
RT R123P) in congenital factor XII deficiency.";
RL Thromb. Haemost. 86:1409-1415(2001).
RN [22]
RP VARIANT FA12D CYS-505, AND CHARACTERIZATION OF VARIANT FA12D CYS-505.
RX PubMed=15205584; DOI=10.1097/01.mbc.0000114447.59147.d1;
RA Ishii K., Oguchi S., Moriki T., Yatabe Y., Takeshita E., Murata M.,
RA Ikeda Y., Watanabe K.;
RT "Genetic analyses and expression studies identified a novel mutation
RT (W486C) as a molecular basis of congenital coagulation factor XII
RT deficiency.";
RL Blood Coagul. Fibrinolysis 15:367-373(2004).
RN [23]
RP VARIANT FA12D THR-411, AND CHARACTERIZATION OF VARIANT FA12D THR-411.
RX PubMed=15617741; DOI=10.1016/j.thromres.2004.08.027;
RA Oguchi S., Ishii K., Moriki T., Takeshita E., Murata M., Ikeda Y.,
RA Watanabe K.;
RT "Factor XII Shizuoka, a novel mutation (Ala392Thr) identified and
RT characterized in a patient with congenital coagulation factor XII
RT deficiency.";
RL Thromb. Res. 115:191-197(2005).
RN [24]
RP VARIANTS HAE3 LYS-328 AND ARG-328.
RX PubMed=16638441; DOI=10.1016/j.bbrc.2006.03.092;
RA Dewald G., Bork K.;
RT "Missense mutations in the coagulation factor XII (Hageman factor) gene in
RT hereditary angioedema with normal C1 inhibitor.";
RL Biochem. Biophys. Res. Commun. 343:1286-1289(2006).
RN [25]
RP VARIANT HAE3 LYS-328.
RX PubMed=17186468; DOI=10.1086/509899;
RA Cichon S., Martin L., Hennies H.C., Mueller F., Van Driessche K.,
RA Karpushova A., Stevens W., Colombo R., Renne T., Drouet C., Bork K.,
RA Noethen M.M.;
RT "Increased activity of coagulation factor XII (Hageman factor) causes
RT hereditary angioedema type III.";
RL Am. J. Hum. Genet. 79:1098-1104(2006).
CC -!- FUNCTION: Factor XII is a serum glycoprotein that participates in the
CC initiation of blood coagulation, fibrinolysis, and the generation of
CC bradykinin and angiotensin. Prekallikrein is cleaved by factor XII to
CC form kallikrein, which then cleaves factor XII first to alpha-factor
CC XIIa and then trypsin cleaves it to beta-factor XIIa. Alpha-factor XIIa
CC activates factor XI to factor XIa. {ECO:0000269|PubMed:21304106}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Selective cleavage of Arg-|-Ile bonds in factor VII to form
CC factor VIIa and factor XI to form factor XIa.; EC=3.4.21.38;
CC -!- SUBUNIT: Interacts with HRG; the interaction, which is enhanced in the
CC presence of zinc ions and inhibited by heparin-binding, inhibits factor
CC XII autoactivation and contact-initiated coagulation.
CC {ECO:0000269|PubMed:21304106}.
CC -!- INTERACTION:
CC P00748; P05067: APP; NbExp=3; IntAct=EBI-6378830, EBI-77613;
CC P00748; Q07021: C1QBP; NbExp=2; IntAct=EBI-6378830, EBI-347528;
CC P00748; P13473-2: LAMP2; NbExp=3; IntAct=EBI-6378830, EBI-21591415;
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- PTM: Factor XII is activated by kallikrein in alpha-factor XIIa, which
CC is further converted by trypsin into beta-factor XIIa. Alpha-factor
CC XIIa is composed of an NH2-terminal heavy chain, called coagulation
CC factor XIIa heavy chain, and a COOH-terminal light chain, called
CC coagulation factor XIIa light chain, connected by a disulfide bond.
CC Beta-factor XIIa is composed of 2 chains linked by a disulfide bond, an
CC N-terminal nonapeptide, called beta-factor XIIa part 1, and coagulation
CC factor XIIa light chain, also known in this context as beta-factor XIIa
CC part 2.
CC -!- PTM: O- and N-glycosylated. The O-linked polysaccharides were not
CC identified, but are probably the mucin type linked to GalNAc.
CC {ECO:0000269|PubMed:14760718, ECO:0000269|PubMed:1544894,
CC ECO:0000269|PubMed:16335952, ECO:0000269|PubMed:3886654}.
CC -!- DISEASE: Factor XII deficiency (FA12D) [MIM:234000]: An asymptomatic
CC anomaly of in vitro blood coagulation. Its diagnosis is based on
CC finding a low plasma activity of the factor in coagulating assays. It
CC is usually only accidentally discovered through pre-operative blood
CC tests. Factor XII deficiency is divided into two categories, a cross-
CC reacting material (CRM)-negative group (negative F12 antigen detection)
CC and a CRM-positive group (positive F12 antigen detection).
CC {ECO:0000269|PubMed:10361128, ECO:0000269|PubMed:11776307,
CC ECO:0000269|PubMed:15205584, ECO:0000269|PubMed:15617741,
CC ECO:0000269|PubMed:2510163, ECO:0000269|PubMed:2882793,
CC ECO:0000269|PubMed:8049433, ECO:0000269|PubMed:8528215,
CC ECO:0000269|PubMed:9354665}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Angioedema, hereditary, 3 (HAE3) [MIM:610618]: A hereditary
CC angioedema occurring only in women. Hereditary angioedema is an
CC autosomal dominant disorder characterized by episodic local swelling
CC involving subcutaneous or submucous tissue of the upper respiratory and
CC gastrointestinal tracts, face, extremities, and genitalia. Hereditary
CC angioedema type 3 differs from types 1 and 2 in that both concentration
CC and function of C1 esterase inhibitor are normal. Hereditary angioedema
CC type 3 is precipitated or worsened by high estrogen levels (e.g.,
CC during pregnancy or treatment with oral contraceptives).
CC {ECO:0000269|PubMed:16638441, ECO:0000269|PubMed:17186468}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the peptidase S1 family. {ECO:0000255|PROSITE-
CC ProRule:PRU00274}.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Factor XII entry;
CC URL="https://en.wikipedia.org/wiki/Factor_XII";
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/f12/";
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DR EMBL; M17466; AAB59490.1; -; Genomic_DNA.
DR EMBL; M17464; AAB59490.1; JOINED; Genomic_DNA.
DR EMBL; M17465; AAB59490.1; JOINED; Genomic_DNA.
DR EMBL; AF538691; AAM97932.1; -; Genomic_DNA.
DR EMBL; AC145098; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; M31315; AAA70225.1; -; mRNA.
DR EMBL; M11723; AAA51986.1; -; mRNA.
DR EMBL; M13147; AAA70224.1; -; mRNA.
DR EMBL; U71274; AAB51203.1; -; Genomic_DNA.
DR CCDS; CCDS34302.1; -.
DR PIR; A29411; KFHU12.
DR RefSeq; NP_000496.2; NM_000505.3.
DR PDB; 4BDW; X-ray; 2.50 A; A=133-215.
DR PDB; 4BDX; X-ray; 1.62 A; A=133-213.
DR PDB; 4XDE; X-ray; 2.14 A; A=373-615.
DR PDB; 4XE4; X-ray; 2.40 A; A=373-615.
DR PDB; 6B74; X-ray; 2.32 A; A=354-362, B=373-615.
DR PDB; 6B77; X-ray; 2.37 A; A=354-362, B=373-615.
DR PDB; 6GT6; X-ray; 2.54 A; B=373-615.
DR PDB; 6L63; X-ray; 3.00 A; A/C=373-615.
DR PDB; 6QF7; X-ray; 4.00 A; B/D=352-615.
DR PDB; 6SZW; X-ray; 3.14 A; D=20-90.
DR PDB; 6X0S; X-ray; 1.90 A; A/B/C=357-615.
DR PDB; 6X0T; X-ray; 1.39 A; A/B/C=357-615.
DR PDB; 7FBP; X-ray; 1.99 A; A=373-613.
DR PDBsum; 4BDW; -.
DR PDBsum; 4BDX; -.
DR PDBsum; 4XDE; -.
DR PDBsum; 4XE4; -.
DR PDBsum; 6B74; -.
DR PDBsum; 6B77; -.
DR PDBsum; 6GT6; -.
DR PDBsum; 6L63; -.
DR PDBsum; 6QF7; -.
DR PDBsum; 6SZW; -.
DR PDBsum; 6X0S; -.
DR PDBsum; 6X0T; -.
DR PDBsum; 7FBP; -.
DR AlphaFoldDB; P00748; -.
DR SMR; P00748; -.
DR BioGRID; 108459; 89.
DR ComplexPortal; CPX-6209; Coagulation factor XIIa complex.
DR IntAct; P00748; 10.
DR STRING; 9606.ENSP00000253496; -.
DR BindingDB; P00748; -.
DR ChEMBL; CHEMBL2821; -.
DR DrugBank; DB09228; Conestat alfa.
DR DrugBank; DB06689; Ethanolamine oleate.
DR DrugBank; DB06404; Human C1-esterase inhibitor.
DR DrugBank; DB12598; Nafamostat.
DR DrugBank; DB01593; Zinc.
DR DrugBank; DB14487; Zinc acetate.
DR GuidetoPHARMACOLOGY; 2361; -.
DR MEROPS; S01.211; -.
DR GlyConnect; 1121; 10 N-Linked glycans (2 sites).
DR GlyGen; P00748; 12 sites, 11 N-linked glycans (2 sites), 4 O-linked glycans (5 sites).
DR iPTMnet; P00748; -.
DR PhosphoSitePlus; P00748; -.
DR BioMuta; F12; -.
DR DMDM; 317373446; -.
DR CPTAC; non-CPTAC-1100; -.
DR CPTAC; non-CPTAC-2650; -.
DR jPOST; P00748; -.
DR MassIVE; P00748; -.
DR PaxDb; P00748; -.
DR PeptideAtlas; P00748; -.
DR PRIDE; P00748; -.
DR ProteomicsDB; 51278; -.
DR ABCD; P00748; 2 sequenced antibodies.
DR Antibodypedia; 864; 759 antibodies from 37 providers.
DR DNASU; 2161; -.
DR Ensembl; ENST00000253496.4; ENSP00000253496.3; ENSG00000131187.10.
DR GeneID; 2161; -.
DR KEGG; hsa:2161; -.
DR MANE-Select; ENST00000253496.4; ENSP00000253496.3; NM_000505.4; NP_000496.2.
DR UCSC; uc003mgo.5; human.
DR CTD; 2161; -.
DR DisGeNET; 2161; -.
DR GeneCards; F12; -.
DR HGNC; HGNC:3530; F12.
DR HPA; ENSG00000131187; Tissue enriched (liver).
DR MalaCards; F12; -.
DR MIM; 234000; phenotype.
DR MIM; 610618; phenotype.
DR MIM; 610619; gene.
DR neXtProt; NX_P00748; -.
DR OpenTargets; ENSG00000131187; -.
DR Orphanet; 330; Congenital factor XII deficiency.
DR Orphanet; 617919; F12-associated cold autoinflammatory syndrome.
DR Orphanet; 100054; F12-related hereditary angioedema with normal C1Inh.
DR Orphanet; 64738; NON RARE IN EUROPE: Non rare thrombophilia.
DR PharmGKB; PA161; -.
DR VEuPathDB; HostDB:ENSG00000131187; -.
DR eggNOG; KOG1217; Eukaryota.
DR eggNOG; KOG3627; Eukaryota.
DR GeneTree; ENSGT00940000161657; -.
DR HOGENOM; CLU_006842_18_1_1; -.
DR InParanoid; P00748; -.
DR OMA; SWEYCDL; -.
DR OrthoDB; 1314811at2759; -.
DR PhylomeDB; P00748; -.
DR TreeFam; TF329901; -.
DR BRENDA; 3.4.21.38; 2681.
DR PathwayCommons; P00748; -.
DR Reactome; R-HSA-140837; Intrinsic Pathway of Fibrin Clot Formation.
DR Reactome; R-HSA-9657688; Defective factor XII causes hereditary angioedema.
DR Reactome; R-HSA-9657689; Defective SERPING1 causes hereditary angioedema.
DR SignaLink; P00748; -.
DR SIGNOR; P00748; -.
DR BioGRID-ORCS; 2161; 5 hits in 1072 CRISPR screens.
DR GeneWiki; Factor_XII; -.
DR GenomeRNAi; 2161; -.
DR Pharos; P00748; Tchem.
DR PRO; PR:P00748; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; P00748; protein.
DR Bgee; ENSG00000131187; Expressed in right lobe of liver and 129 other tissues.
DR Genevisible; P00748; HS.
DR GO; GO:0062023; C:collagen-containing extracellular matrix; HDA:BHF-UCL.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0005791; C:rough endoplasmic reticulum; IBA:GO_Central.
DR GO; GO:1905370; C:serine-type endopeptidase complex; IC:ComplexPortal.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0051787; F:misfolded protein binding; IC:BHF-UCL.
DR GO; GO:0004252; F:serine-type endopeptidase activity; IDA:BHF-UCL.
DR GO; GO:0007596; P:blood coagulation; IBA:GO_Central.
DR GO; GO:0007597; P:blood coagulation, intrinsic pathway; IC:BHF-UCL.
DR GO; GO:0002542; P:Factor XII activation; IDA:BHF-UCL.
DR GO; GO:0042730; P:fibrinolysis; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; TAS:BHF-UCL.
DR GO; GO:0002353; P:plasma kallikrein-kinin cascade; IDA:BHF-UCL.
DR GO; GO:0030194; P:positive regulation of blood coagulation; IDA:BHF-UCL.
DR GO; GO:0051919; P:positive regulation of fibrinolysis; IDA:BHF-UCL.
DR GO; GO:0010756; P:positive regulation of plasminogen activation; IDA:BHF-UCL.
DR GO; GO:0016540; P:protein autoprocessing; IDA:BHF-UCL.
DR GO; GO:0016485; P:protein processing; IDA:BHF-UCL.
DR GO; GO:0006508; P:proteolysis; IDA:ComplexPortal.
DR GO; GO:0051788; P:response to misfolded protein; IDA:BHF-UCL.
DR GO; GO:0031638; P:zymogen activation; IDA:BHF-UCL.
DR CDD; cd00061; FN1; 1.
DR CDD; cd00062; FN2; 1.
DR CDD; cd00108; KR; 1.
DR CDD; cd00190; Tryp_SPc; 1.
DR Gene3D; 2.10.10.10; -; 1.
DR Gene3D; 2.40.10.10; -; 2.
DR Gene3D; 2.40.20.10; -; 1.
DR InterPro; IPR014394; Coagulation_fac_XII/HGFA.
DR InterPro; IPR001881; EGF-like_Ca-bd_dom.
DR InterPro; IPR000742; EGF-like_dom.
DR InterPro; IPR000083; Fibronectin_type1.
DR InterPro; IPR000562; FN_type2_dom.
DR InterPro; IPR036943; FN_type2_sf.
DR InterPro; IPR000001; Kringle.
DR InterPro; IPR013806; Kringle-like.
DR InterPro; IPR018056; Kringle_CS.
DR InterPro; IPR038178; Kringle_sf.
DR InterPro; IPR009003; Peptidase_S1_PA.
DR InterPro; IPR043504; Peptidase_S1_PA_chymotrypsin.
DR InterPro; IPR001314; Peptidase_S1A.
DR InterPro; IPR001254; Trypsin_dom.
DR InterPro; IPR018114; TRYPSIN_HIS.
DR InterPro; IPR033116; TRYPSIN_SER.
DR Pfam; PF00008; EGF; 2.
DR Pfam; PF00039; fn1; 1.
DR Pfam; PF00040; fn2; 1.
DR Pfam; PF00051; Kringle; 1.
DR Pfam; PF00089; Trypsin; 1.
DR PIRSF; PIRSF001146; Factor_XII_HGFA; 1.
DR PRINTS; PR00722; CHYMOTRYPSIN.
DR SMART; SM00181; EGF; 2.
DR SMART; SM00179; EGF_CA; 2.
DR SMART; SM00058; FN1; 1.
DR SMART; SM00059; FN2; 1.
DR SMART; SM00130; KR; 1.
DR SMART; SM00020; Tryp_SPc; 1.
DR SUPFAM; SSF50494; SSF50494; 1.
DR SUPFAM; SSF57440; SSF57440; 2.
DR PROSITE; PS00022; EGF_1; 2.
DR PROSITE; PS01186; EGF_2; 1.
DR PROSITE; PS50026; EGF_3; 2.
DR PROSITE; PS01253; FN1_1; 1.
DR PROSITE; PS51091; FN1_2; 1.
DR PROSITE; PS00023; FN2_1; 1.
DR PROSITE; PS51092; FN2_2; 1.
DR PROSITE; PS00021; KRINGLE_1; 1.
DR PROSITE; PS50070; KRINGLE_2; 1.
DR PROSITE; PS50240; TRYPSIN_DOM; 1.
DR PROSITE; PS00134; TRYPSIN_HIS; 1.
DR PROSITE; PS00135; TRYPSIN_SER; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Blood coagulation; Direct protein sequencing;
KW Disease variant; Disulfide bond; EGF-like domain; Fibrinolysis;
KW Glycoprotein; Hemostasis; Hydrolase; Kringle; Protease; Reference proteome;
KW Repeat; Secreted; Serine protease; Signal; Zymogen.
FT SIGNAL 1..19
FT /evidence="ECO:0000269|PubMed:3886654"
FT CHAIN 20..372
FT /note="Coagulation factor XIIa heavy chain"
FT /id="PRO_0000027833"
FT CHAIN 354..362
FT /note="Beta-factor XIIa part 1"
FT /id="PRO_0000027834"
FT CHAIN 373..615
FT /note="Coagulation factor XIIa light chain"
FT /id="PRO_0000027835"
FT DOMAIN 42..90
FT /note="Fibronectin type-II"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00478,
FT ECO:0000255|PROSITE-ProRule:PRU00479"
FT DOMAIN 94..131
FT /note="EGF-like 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 133..173
FT /note="Fibronectin type-I"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00478"
FT DOMAIN 174..210
FT /note="EGF-like 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 217..295
FT /note="Kringle"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00121"
FT DOMAIN 373..614
FT /note="Peptidase S1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00274"
FT REGION 298..359
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 302..332
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 412
FT /note="Charge relay system"
FT /evidence="ECO:0000250"
FT ACT_SITE 461
FT /note="Charge relay system"
FT /evidence="ECO:0000250"
FT ACT_SITE 563
FT /note="Charge relay system"
FT /evidence="ECO:0000250"
FT CARBOHYD 109
FT /note="O-linked (Fuc) threonine"
FT /evidence="ECO:0000269|PubMed:1544894"
FT CARBOHYD 249
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16335952,
FT ECO:0000269|PubMed:3877053, ECO:0000269|PubMed:3886654"
FT CARBOHYD 299
FT /note="O-linked (GalNAc...) threonine"
FT /evidence="ECO:0000269|PubMed:3886654"
FT CARBOHYD 305
FT /note="O-linked (GalNAc...) threonine"
FT /evidence="ECO:0000269|PubMed:3886654"
FT CARBOHYD 308
FT /note="O-linked (GalNAc...) serine"
FT /evidence="ECO:0000269|PubMed:3886654"
FT CARBOHYD 328
FT /note="O-linked (GalNAc...) threonine"
FT /evidence="ECO:0000269|PubMed:3886654"
FT CARBOHYD 329
FT /note="O-linked (GalNAc...) threonine"
FT /evidence="ECO:0000269|PubMed:3886654"
FT CARBOHYD 337
FT /note="O-linked (GalNAc...) threonine"
FT /evidence="ECO:0000269|PubMed:3886654"
FT CARBOHYD 433
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:14760718,
FT ECO:0000269|PubMed:16335952"
FT DISULFID 47..73
FT /evidence="ECO:0000250"
FT DISULFID 61..88
FT /evidence="ECO:0000250"
FT DISULFID 98..110
FT /evidence="ECO:0000250"
FT DISULFID 104..119
FT /evidence="ECO:0000250"
FT DISULFID 121..130
FT /evidence="ECO:0000250"
FT DISULFID 135..163
FT /evidence="ECO:0000269|PubMed:23385745"
FT DISULFID 161..170
FT /evidence="ECO:0000269|PubMed:23385745"
FT DISULFID 178..189
FT /evidence="ECO:0000269|PubMed:23385745"
FT DISULFID 183..198
FT /evidence="ECO:0000269|PubMed:23385745"
FT DISULFID 200..209
FT /evidence="ECO:0000269|PubMed:23385745"
FT DISULFID 217..295
FT /evidence="ECO:0000250"
FT DISULFID 238..277
FT /evidence="ECO:0000250"
FT DISULFID 266..290
FT /evidence="ECO:0000250"
FT DISULFID 359..486
FT /evidence="ECO:0000250"
FT DISULFID 397..413
FT /evidence="ECO:0000250"
FT DISULFID 405..475
FT /evidence="ECO:0000250"
FT DISULFID 436..439
FT /evidence="ECO:0000250"
FT DISULFID 500..569
FT /evidence="ECO:0000250"
FT DISULFID 532..548
FT /evidence="ECO:0000250"
FT DISULFID 559..590
FT /evidence="ECO:0000250"
FT VARIANT 53
FT /note="Y -> C (in FA12D; Tenri; inactive;
FT dbSNP:rs118204455)"
FT /evidence="ECO:0000269|PubMed:10361128"
FT /id="VAR_014426"
FT VARIANT 142
FT /note="R -> P (in FA12D; CRM-negative phenotype; low levels
FT of accumulation in the cell; not secreted)"
FT /evidence="ECO:0000269|PubMed:11776307"
FT /id="VAR_031500"
FT VARIANT 207
FT /note="A -> P (in dbSNP:rs17876030)"
FT /evidence="ECO:0000269|PubMed:2888762,
FT ECO:0000269|PubMed:3011063, ECO:0000269|PubMed:3754331,
FT ECO:0000269|PubMed:3877053, ECO:0000269|PubMed:3886654,
FT ECO:0000269|Ref.2"
FT /id="VAR_014336"
FT VARIANT 328
FT /note="T -> K (in HAE3; dbSNP:rs118204456)"
FT /evidence="ECO:0000269|PubMed:16638441,
FT ECO:0000269|PubMed:17186468"
FT /id="VAR_031501"
FT VARIANT 328
FT /note="T -> R (in HAE3; dbSNP:rs118204456)"
FT /evidence="ECO:0000269|PubMed:16638441"
FT /id="VAR_031502"
FT VARIANT 342
FT /note="P -> Q (in dbSNP:rs2230939)"
FT /id="VAR_029191"
FT VARIANT 372
FT /note="R -> P (in FA12D; Locarno; inactive;
FT dbSNP:rs118204454)"
FT /evidence="ECO:0000269|PubMed:8049433"
FT /id="VAR_006623"
FT VARIANT 411
FT /note="A -> T (in FA12D; Shizuoka; CRM-negative phenotype;
FT transcribed and synthesized at wild-type levels; not
FT secreted; dbSNP:rs865853663)"
FT /evidence="ECO:0000269|PubMed:15617741"
FT /id="VAR_031503"
FT VARIANT 414
FT /note="L -> M (in FA12D; CRM-negative phenotype)"
FT /evidence="ECO:0000269|PubMed:9354665"
FT /id="VAR_031504"
FT VARIANT 417
FT /note="R -> Q (in FA12D; CRM-negative phenotype;
FT dbSNP:rs932430490)"
FT /evidence="ECO:0000269|PubMed:9354665"
FT /id="VAR_031505"
FT VARIANT 440
FT /note="Q -> K (in FA12D; CRM-negative phenotype;
FT accumulation in the cell; low secretion)"
FT /evidence="ECO:0000269|PubMed:11776307"
FT /id="VAR_031506"
FT VARIANT 461
FT /note="D -> N (in FA12D; CRM-positive phenotype)"
FT /evidence="ECO:0000269|PubMed:9354665"
FT /id="VAR_031507"
FT VARIANT 505
FT /note="W -> C (in FA12D; CRM-negative phenotype;
FT transcribed and synthesized at wild-type levels; not
FT secreted)"
FT /evidence="ECO:0000269|PubMed:15205584"
FT /id="VAR_031508"
FT VARIANT 545
FT /note="G -> D (in dbSNP:rs17876034)"
FT /evidence="ECO:0000269|Ref.2"
FT /id="VAR_014337"
FT VARIANT 589
FT /note="G -> R (in FA12D; CRM-positive phenotype;
FT dbSNP:rs766505234)"
FT /evidence="ECO:0000269|PubMed:8528215,
FT ECO:0000269|PubMed:9354665"
FT /id="VAR_031509"
FT VARIANT 590
FT /note="C -> S (in FA12D; Washington D.C.; inactive;
FT dbSNP:rs1157280571)"
FT /evidence="ECO:0000269|PubMed:2510163"
FT /id="VAR_006624"
FT VARIANT 605
FT /note="Y -> H (in dbSNP:rs17876035)"
FT /evidence="ECO:0000269|Ref.2"
FT /id="VAR_014338"
FT CONFLICT 333
FT /note="P -> S (in Ref. 5; AAA51986)"
FT /evidence="ECO:0000305"
FT CONFLICT 379
FT /note="A -> G (in Ref. 6; AAA70224)"
FT /evidence="ECO:0000305"
FT HELIX 42..44
FT /evidence="ECO:0007829|PDB:6SZW"
FT STRAND 49..53
FT /evidence="ECO:0007829|PDB:6SZW"
FT STRAND 56..60
FT /evidence="ECO:0007829|PDB:6SZW"
FT STRAND 75..78
FT /evidence="ECO:0007829|PDB:6SZW"
FT HELIX 79..82
FT /evidence="ECO:0007829|PDB:6SZW"
FT STRAND 86..88
FT /evidence="ECO:0007829|PDB:6SZW"
FT STRAND 135..137
FT /evidence="ECO:0007829|PDB:4BDX"
FT TURN 138..141
FT /evidence="ECO:0007829|PDB:4BDX"
FT STRAND 142..144
FT /evidence="ECO:0007829|PDB:4BDX"
FT STRAND 149..153
FT /evidence="ECO:0007829|PDB:4BDX"
FT STRAND 158..163
FT /evidence="ECO:0007829|PDB:4BDX"
FT STRAND 165..173
FT /evidence="ECO:0007829|PDB:4BDX"
FT STRAND 188..192
FT /evidence="ECO:0007829|PDB:4BDX"
FT STRAND 195..199
FT /evidence="ECO:0007829|PDB:4BDX"
FT STRAND 204..206
FT /evidence="ECO:0007829|PDB:4BDX"
FT STRAND 380..383
FT /evidence="ECO:0007829|PDB:4XDE"
FT STRAND 387..392
FT /evidence="ECO:0007829|PDB:6X0T"
FT STRAND 395..403
FT /evidence="ECO:0007829|PDB:6X0T"
FT STRAND 406..409
FT /evidence="ECO:0007829|PDB:6X0T"
FT HELIX 411..414
FT /evidence="ECO:0007829|PDB:6X0T"
FT HELIX 420..422
FT /evidence="ECO:0007829|PDB:6X0T"
FT STRAND 424..428
FT /evidence="ECO:0007829|PDB:6X0T"
FT STRAND 430..434
FT /evidence="ECO:0007829|PDB:6X0T"
FT STRAND 440..449
FT /evidence="ECO:0007829|PDB:6X0T"
FT TURN 455..457
FT /evidence="ECO:0007829|PDB:6X0T"
FT STRAND 463..467
FT /evidence="ECO:0007829|PDB:6X0T"
FT TURN 471..473
FT /evidence="ECO:0007829|PDB:4XE4"
FT STRAND 490..492
FT /evidence="ECO:0007829|PDB:4XDE"
FT STRAND 500..506
FT /evidence="ECO:0007829|PDB:6X0T"
FT HELIX 513..515
FT /evidence="ECO:0007829|PDB:4XDE"
FT STRAND 520..523
FT /evidence="ECO:0007829|PDB:6X0T"
FT HELIX 529..532
FT /evidence="ECO:0007829|PDB:6X0T"
FT TURN 535..538
FT /evidence="ECO:0007829|PDB:6X0T"
FT HELIX 539..541
FT /evidence="ECO:0007829|PDB:6X0T"
FT STRAND 546..550
FT /evidence="ECO:0007829|PDB:6X0T"
FT TURN 558..560
FT /evidence="ECO:0007829|PDB:4XDE"
FT STRAND 566..570
FT /evidence="ECO:0007829|PDB:6X0T"
FT HELIX 572..574
FT /evidence="ECO:0007829|PDB:6X0T"
FT STRAND 578..586
FT /evidence="ECO:0007829|PDB:6X0T"
FT STRAND 588..591
FT /evidence="ECO:0007829|PDB:6X0T"
FT STRAND 597..601
FT /evidence="ECO:0007829|PDB:6X0T"
FT HELIX 602..605
FT /evidence="ECO:0007829|PDB:6X0T"
FT HELIX 606..612
FT /evidence="ECO:0007829|PDB:6X0T"
SQ SEQUENCE 615 AA; 67792 MW; F5B861BF635EB480 CRC64;
MRALLLLGFL LVSLESTLSI PPWEAPKEHK YKAEEHTVVL TVTGEPCHFP FQYHRQLYHK
CTHKGRPGPQ PWCATTPNFD QDQRWGYCLE PKKVKDHCSK HSPCQKGGTC VNMPSGPHCL
CPQHLTGNHC QKEKCFEPQL LRFFHKNEIW YRTEQAAVAR CQCKGPDAHC QRLASQACRT
NPCLHGGRCL EVEGHRLCHC PVGYTGAFCD VDTKASCYDG RGLSYRGLAR TTLSGAPCQP
WASEATYRNV TAEQARNWGL GGHAFCRNPD NDIRPWCFVL NRDRLSWEYC DLAQCQTPTQ
AAPPTPVSPR LHVPLMPAQP APPKPQPTTR TPPQSQTPGA LPAKREQPPS LTRNGPLSCG
QRLRKSLSSM TRVVGGLVAL RGAHPYIAAL YWGHSFCAGS LIAPCWVLTA AHCLQDRPAP
EDLTVVLGQE RRNHSCEPCQ TLAVRSYRLH EAFSPVSYQH DLALLRLQED ADGSCALLSP
YVQPVCLPSG AARPSETTLC QVAGWGHQFE GAEEYASFLQ EAQVPFLSLE RCSAPDVHGS
SILPGMLCAG FLEGGTDACQ GDSGGPLVCE DQAAERRLTL QGIISWGSGC GDRNKPGVYT
DVAYYLAWIR EHTVS
