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 27-MAR-2024, entry version 252. 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 INTERACTION WITH MOSQUITO D7L2. RX PubMed=35460690; DOI=10.1016/j.jbc.2022.101971; RA Smith L.B., Duge E., Valenzuela-Leon P.C., Brooks S., Martin-Martin I., RA Ackerman H., Calvo E.; RT "Novel salivary antihemostatic activities of long-form D7 proteins from the RT malaria vector Anopheles gambiae facilitate hematophagy."; RL J. Biol. Chem. 298:101971-101971(2022). RN [17] 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 [18] 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 [19] 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 [20] 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 [21] 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 [22] 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 [23] 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 [24] 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 [25] 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 [26] 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. Interacts CC (inactive and activated) with Anopheles gambiae D7L2 (PubMed:35460690). CC {ECO:0000269|PubMed:21304106, ECO:0000269|PubMed:35460690}. 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/"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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 PDB; 7PRJ; X-ray; 1.20 A; A=20-90. DR PDB; 7PRK; X-ray; 1.64 A; A=20-90. 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 PDBsum; 7PRJ; -. DR PDBsum; 7PRK; -. 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 GlyCosmos; P00748; 12 sites, 14 glycans. DR GlyGen; P00748; 13 sites, 11 N-linked glycans (2 sites), 5 O-linked glycans (6 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; 9606-ENSP00000253496; -. DR PeptideAtlas; P00748; -. DR ProteomicsDB; 51278; -. DR ABCD; P00748; 2 sequenced antibodies. DR Antibodypedia; 864; 940 antibodies from 37 providers. DR DNASU; 2161; -. DR Ensembl; ENST00000253496.4; ENSP00000253496.3; ENSG00000131187.11. 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 AGR; HGNC:3530; -. 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; GPQPWCA; -. DR OrthoDB; 4629979at2759; -. DR PhylomeDB; P00748; -. DR TreeFam; TF329901; -. DR BioCyc; MetaCyc:HS05500-MONOMER; -. 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 1156 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 131 other cell types or tissues. 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: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:0051788; P:response to misfolded protein; IDA:BHF-UCL. DR GO; GO:0031638; P:zymogen activation; IDA:BHF-UCL. DR CDD; cd00054; EGF_CA; 2. 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; Fibronectin, type II, collagen-binding; 1. DR Gene3D; 2.10.25.10; Laminin; 2. DR Gene3D; 2.40.20.10; Plasminogen Kringle 4; 1. DR Gene3D; 2.40.10.10; Trypsin-like serine proteases; 2. 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 PANTHER; PTHR24264:SF46; COAGULATION FACTOR XII; 1. DR PANTHER; PTHR24264; TRYPSIN-RELATED; 1. 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 PRINTS; PR00013; FNTYPEII. DR PRINTS; PR00018; KRINGLE. 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; SSF57196; EGF/Laminin; 1. DR SUPFAM; SSF57440; Kringle-like; 2. DR SUPFAM; SSF50494; Trypsin-like serine proteases; 1. 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. DR Genevisible; P00748; HS. 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 //