ID IC1_HUMAN STANDARD; PRT; 500 AA. AC P05155; Q96FE0; DT 13-AUG-1987 (Rel. 05, Created) DT 01-FEB-1991 (Rel. 17, Last sequence update) DT 10-MAY-2005 (Rel. 47, Last annotation update) DE Plasma protease C1 inhibitor precursor (C1 Inh) (C1Inh). GN Name=SERPING1; Synonyms=C1IN, C1NH; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE. RX MEDLINE=88185313; PubMed=3267220; RA Carter P.E., Dunbar B., Fothergill J.E.; RT "Genomic and cDNA cloning of the human C1 inhibitor. Intron-exon RT junctions and comparison with other serpins."; RL Eur. J. Biochem. 173:163-169(1988). RN [2] RP NUCLEOTIDE SEQUENCE. RX MEDLINE=91224119; PubMed=2026152; RA Carter P.E., Duponchel C., Tosi M., Fothergill J.E.; RT "Complete nucleotide sequence of the gene for human C1 inhibitor with RT an unusually high density of Alu elements."; RL Eur. J. Biochem. 197:301-308(1991). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA], AND PARTIAL PROTEIN SEQUENCE. RX MEDLINE=87000544; PubMed=3756141; RA Bock S.C., Skriver K., Nielsen E., Thoegersen H.-C., Wiman B., RA Donaldson V.H., Eddy R.L., Marrinan J., Radziejewska E., Huber R., RA Shows T.B., Magnusson S.; RT "Human C1 inhibitor: primary structure, cDNA cloning, and chromosomal RT localization."; RL Biochemistry 25:4292-4301(1986). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA]. RX MEDLINE=86268965; PubMed=3488058; RA Que B.G., Petra P.H.; RT "Isolation and analysis of a cDNA coding for human C1 inhibitor."; RL Biochem. Biophys. Res. Commun. 137:620-625(1986). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT MET-480. RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor RT vector."; RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT MET-480. RA Rieder M.J., Johanson E.J., da Ponte S.H., Hastings N.C., Ahearn M.O., RA Bertucci C.B., Wong M.W., Yi Q., Nickerson D.A.; RT "SeattleSNPs. NHLBI HL66682 program for genomic applications, UW- RT FHCRC, Seattle, WA (URL: http://pga.gs.washington.edu)."; RL Submitted (JAN-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT MET-480. RC TISSUE=Brain; RX MEDLINE=22388257; PubMed=12477932; DOI=10.1073/pnas.242603899; RA Strausberg R.L., Feingold E.A., Grouse L.H., Derge J.G., RA Klausner R.D., Collins F.S., Wagner L., Shenmen C.M., Schuler G.D., RA Altschul S.F., Zeeberg B., Buetow K.H., Schaefer C.F., Bhat N.K., RA Hopkins R.F., Jordan H., Moore T., Max S.I., Wang J., Hsieh F., RA Diatchenko L., Marusina K., Farmer A.A., Rubin G.M., Hong L., RA Stapleton M., Soares M.B., Bonaldo M.F., Casavant T.L., Scheetz T.E., RA Brownstein M.J., Usdin T.B., Toshiyuki S., Carninci P., Prange C., RA Raha S.S., Loquellano N.A., Peters G.J., Abramson R.D., Mullahy S.J., RA Bosak S.A., McEwan P.J., McKernan K.J., Malek J.A., Gunaratne P.H., RA Richards S., Worley K.C., Hale S., Garcia A.M., Gay L.J., Hulyk S.W., RA Villalon D.K., Muzny D.M., Sodergren E.J., Lu X., Gibbs R.A., RA Fahey J., Helton E., Ketteman M., Madan A., Rodrigues S., Sanchez A., RA Whiting M., Madan A., Young A.C., Shevchenko Y., Bouffard G.G., RA Blakesley R.W., Touchman J.W., Green E.D., Dickson M.C., RA Rodriguez A.C., Grimwood J., Schmutz J., Myers R.M., RA Butterfield Y.S.N., Krzywinski M.I., Skalska U., Smailus D.E., RA Schnerch A., Schein J.E., Jones S.J.M., Marra M.A.; RT "Generation and initial analysis of more than 15,000 full-length human RT and mouse cDNA sequences."; RL Proc. Natl. Acad. Sci. U.S.A. 99:16899-16903(2002). RN [8] RP NUCLEOTIDE SEQUENCE OF 6-500. RX MEDLINE=88276848; PubMed=3393514; RA Rauth G., Schumacher G., Buckel P., Mueller-Esterl W.; RT "Molecular cloning of the cDNA coding for human C1 inhibitor."; RL Protein Seq. Data Anal. 1:251-257(1988). RN [9] RP NUCLEOTIDE SEQUENCE OF 213-500. RX MEDLINE=86276001; PubMed=3089875; DOI=10.1016/0378-1119(86)90230-1; RA Tosi M., Duponchel C., Bourgarel P., Colomb M., Meo T.; RT "Molecular cloning of human C1 inhibitor: sequence homologies with RT alpha 1-antitrypsin and other members of the serpins superfamily."; RL Gene 42:265-272(1986). RN [10] RP NUCLEOTIDE SEQUENCE [MRNA] OF 241-458, AND PARTIAL PROTEIN SEQUENCE. RX MEDLINE=86205856; PubMed=3458172; RA Davis A.E. III, Whitehead A.S., Harrison R.A., Dauphinias A., RA Bruns G.A., Cicardi M., Rosen F.S.; RT "Human inhibitor of the first component of complement, C1: RT characterization of cDNA clones and localization of the gene to RT chromosome 11."; RL Proc. Natl. Acad. Sci. U.S.A. 83:3161-3165(1986). RN [11] RP NUCLEOTIDE SEQUENCE OF 33-228. RX MEDLINE=90160364; PubMed=2154751; RA Stoppa-Lyonnet D., Carter P.E., Meo T., Tosi M.; RT "Clusters of intragenic Alu repeats predispose the human C1 inhibitor RT locus to deleterious rearrangements."; RL Proc. Natl. Acad. Sci. U.S.A. 87:1551-1555(1990). RN [12] RP PROTEIN SEQUENCE OF 23-62. RX MEDLINE=84053355; PubMed=6416294; RA Harrison R.; RT "Human C1 inhibitor: improved isolation and preliminary structural RT characterization."; RL Biochemistry 22:5001-5007(1983). RN [13] RP CARBOHYDRATE-LINKAGE SITE ASN-253. RX MEDLINE=22660472; PubMed=12754519; DOI=10.1038/nbt827; RA Zhang H., Li X.-J., Martin D.B., Aebersold R.; RT "Identification and quantification of N-linked glycoproteins using RT hydrazide chemistry, stable isotope labeling and mass spectrometry."; RL Nat. Biotechnol. 21:660-666(2003). RN [14] RP REVIEW ON VARIANTS. RX MEDLINE=95269065; PubMed=7749926; RA Stein P.E., Carrell R.W.; RT "What do dysfunctional serpins tell us about molecular mobility and RT disease?"; RL Nat. Struct. Biol. 2:96-113(1995). RN [15] RP VARIANT HANE HIS-466. RX MEDLINE=89025602; PubMed=3178731; RA Aulak K.S., Pemberton P.A., Rosen F.S., Carrell R.W., Lachmann P.J., RA Harrison R.A.; RT "Dysfunctional C1-inhibitor(At), isolated from a type II hereditary- RT angio-oedema plasma, contains a P1 'reactive centre' (Arg444-->His) RT mutation."; RL Biochem. J. 253:615-618(1988). RN [16] RP VARIANT HANE SER-466. RX MEDLINE=90306337; PubMed=2365061; DOI=10.1016/0014-5793(90)81494-9; RA Aulak K.S., Cicardi M., Harrison R.A.; RT "Identification of a new P1 residue mutation (444Arg-->Ser) in a RT dysfunctional C1 inhibitor protein contained in a type II hereditary RT angioedema plasma."; RL FEBS Lett. 266:13-16(1990). RN [17] RP VARIANT HANE THR-458. RX MEDLINE=90115854; PubMed=2296585; RA Levy N.J., Ramesh N., Cicardi M., Harrison R.A., Davis A.; RT "Type II hereditary angioneurotic edema that may result from a single RT nucleotide change in the codon for alanine-436 in the C1 inhibitor RT gene."; RL Proc. Natl. Acad. Sci. U.S.A. 87:265-268(1990). RN [18] RP VARIANT HANE LYS-273 DEL. RX MEDLINE=90370868; PubMed=2118657; RA Parad R.B., Kramer J., Strunk R.C., Rosen F.S., Davis A.E.; RT "Dysfunctional C1 inhibitor Ta: deletion of Lys-251 results in RT acquisition of an N-glycosylation site."; RL Proc. Natl. Acad. Sci. U.S.A. 87:6786-6790(1990). RN [19] RP VARIANTS HANE GLU-456 AND VAL-458. RA Siddique Z.M., McPhaden A.R., Whaley K.; RT "Identification of type II hereditary angio-oedema (HAE) mutations."; RL Clin. Exp. Immunol. 86:11-12(1991). RN [20] RP VARIANT HANE LEU-466. RX MEDLINE=93083618; PubMed=1451784; DOI=10.1016/0014-5793(92)80204-T; RA Frange D., Aulak K.S., Cicardi M., Harrison R.A., Davis A.E. III; RT "A dysfunctional C1 inhibitor protein with a new reactive center RT mutation (Arg-444-->Leu)."; RL FEBS Lett. 301:34-36(1992). RN [21] RP VARIANTS HANE GLU-454 AND THR-458. RX MEDLINE=93251025; PubMed=1363816; RA Davis A.E. III, Aulak K., Parad R.B., Stecklein H.P., Eldering E., RA Hack C.E., Kramer J., Strunk R.C., Bissler J., Rosen F.S.; RT "C1 inhibitor hinge region mutations produce dysfunction by different RT mechanisms."; RL Nat. Genet. 1:354-358(1992). RN [22] RP VARIANT HANE ARG-429. RX MEDLINE=94226584; PubMed=8172583; RA Davies A.E., Bissler J.J., Cicardi M.; RT "Mutations in the C1 inhibitor gene that result in hereditary RT angioneurotic edema."; RL Behring Inst. Mitt. 93:313-320(1993). RN [23] RP VARIANTS HANE MET-473; ARG-481; PRO-481; ARG-489 AND SER-498. RX MEDLINE=95114132; PubMed=7814636; RA Verpy E., Couture-Tosi E., Eldering E., Lopez-Trascasa M., Spath P., RA Meo T., Tosi M.; RT "Crucial residues in the carboxy-terminal end of C1 inhibitor revealed RT by pathogenic mutants impaired in secretion or function."; RL J. Clin. Invest. 95:350-359(1995). RN [24] RP VARIANT HANE VAL-465. RX MEDLINE=95190028; PubMed=7883978; RA Zahedi R., Bissler J.J., Davis A.E. III, Andreadis C., Wisnieski J.J.; RT "Unique C1 inhibitor dysfunction in a kindred without angioedema. II. RT Identification of an Ala443-->Val substitution and functional analysis RT of the recombinant mutant protein."; RL J. Clin. Invest. 95:1299-1305(1995). RN [25] RP VARIANT HANE PRO-467. RX MEDLINE=96091393; PubMed=8529136; RA Ocejo-Vinyals J.G., Leyva-Cobian F., Fernandez-Luna J.L.; RT "A mutation unique in serine protease inhibitors (serpins) identified RT in a family with type II hereditary angioneurotic edema."; RL Mol. Med. 1:700-705(1995). RN [26] RP VARIANTS HANE. RX MEDLINE=96335700; PubMed=8755917; RA Verpy E., Biasotto M., Brai M., Misiano G., Meo T., Tosi M.; RT "Exhaustive mutation scanning by fluorescence-assisted mismatch RT analysis discloses new genotype-phenotype correlations in angiodema."; RL Am. J. Hum. Genet. 59:308-319(1996). CC -!- FUNCTION: Activation of the C1 complex is under control of the C1- CC inhibitor. It forms a proteolytically inactive stoichiometric CC complex with the C1r or C1s proteases. May play a potentially CC crucial role in regulating important physiological pathways CC including complement activation, blood coagulation, fibrinolysis CC and the generation of kinins. CC -!- SUBCELLULAR LOCATION: Secreted. CC -!- PTM: Highly glycosylated (49%). CC -!- POLYMORPHISM: There are two alleles. CC -!- DISEASE: Defects in SERPING1 are the cause of hereditary CC angioneurotic edema (HANE) [MIM:106100]; also called hereditary CC angioedema (HAE) or type II hereditary angioedema (type-II HAE). CC HANE is an autosomal dominant disorder characterized by episodic CC local subcutaneous edema and submucosal edema involving the upper CC respiratory and gastrointestinal tracts. There are 2 types of the CC disorder. In type I, representing 85% of patients, serum levels of CC C1NH are less than 35% of normal. In type II, the levels are CC normal or elevated, but the protein is nonfunctional. CC -!- SIMILARITY: Belongs to the serpin family. 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; X07577; CAA30469.1; -; mRNA. DR EMBL; X54486; CAA38358.1; -; Genomic_DNA. DR EMBL; X07427; CAA30314.1; -; Genomic_DNA. DR EMBL; X07428; CAA30314.1; JOINED; Genomic_DNA. DR EMBL; X07429; CAA30314.1; JOINED; Genomic_DNA. DR EMBL; X07430; CAA30314.1; JOINED; Genomic_DNA. DR EMBL; X07431; CAA30314.1; JOINED; Genomic_DNA. DR EMBL; X07432; CAA30314.1; JOINED; Genomic_DNA. DR EMBL; X07433; CAA30314.1; JOINED; Genomic_DNA. DR EMBL; M14036; AAA51848.1; -; mRNA. DR EMBL; BT006966; AAP35612.1; -; mRNA. DR EMBL; AY904027; AAW69393.1; -; Genomic_DNA. DR EMBL; BC011171; AAH11171.1; -; mRNA. DR EMBL; M13656; AAB59387.1; -; mRNA. DR EMBL; M13203; AAA51849.1; -; mRNA. DR EMBL; M13690; AAA35613.1; -; mRNA. DR EMBL; M30688; AAA53096.1; ALT_SEQ; Genomic_DNA. DR PIR; S15386; ITHUC1. DR PDB; 1M6Q; Model; A=138-500. DR Ensembl; ENSG00000149131; Homo sapiens. DR HGNC; HGNC:1228; SERPING1. DR H-InvDB; HIX0009638; -. DR Reactome; P05155; -. DR MIM; 606860; -. DR MIM; 106100; -. DR GO; GO:0005576; C:extracellular region; NAS. DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; TAS. DR GO; GO:0008015; P:circulation; TAS. DR InterPro; IPR000215; Prot_inh_serpin. DR Pfam; PF00079; Serpin; 1. DR PROSITE; PS00284; SERPIN; 1. KW 3D-structure; Blood coagulation; Complement pathway; KW Direct protein sequencing; Disease mutation; Glycoprotein; KW Immune response; Innate immunity; Plasma; Polymorphism; KW Protease inhibitor; Repeat; Serine protease inhibitor; Serpin; Signal. FT SIGNAL 1 22 FT CHAIN 23 500 Plasma protease C1 inhibitor. FT REPEAT 85 88 1. FT REPEAT 89 92 2. FT REPEAT 93 96 3. FT REPEAT 97 100 4. FT REPEAT 101 104 5. FT REPEAT 105 108 6. FT REPEAT 116 119 7. FT REGION 85 119 7 X 4 AA tandem repeats of [QE]-P-T-[TQ]. FT SITE 466 467 Reactive bond. FT CARBOHYD 25 25 N-linked (GlcNAc...). FT CARBOHYD 48 48 O-linked. FT CARBOHYD 64 64 O-linked. FT CARBOHYD 69 69 N-linked (GlcNAc...). FT CARBOHYD 71 71 O-linked. FT CARBOHYD 81 81 N-linked (GlcNAc...). FT CARBOHYD 83 83 O-linked. FT CARBOHYD 88 88 O-linked. FT CARBOHYD 92 92 O-linked. FT CARBOHYD 96 96 O-linked. FT CARBOHYD 238 238 N-linked (GlcNAc...). FT CARBOHYD 253 253 N-linked (GlcNAc...). FT CARBOHYD 272 272 N-linked (GlcNAc...); in variant TA. FT CARBOHYD 352 352 N-linked (GlcNAc...). FT DISULFID 123 428 FT DISULFID 130 205 FT VARIANT 273 273 Missing (in HANE; type-II; TA; creates a FT new glycosylation site). FT /FTId=VAR_007012. FT VARIANT 308 308 T -> S (in dbSNP:1803212). FT /FTId=VAR_011751. FT VARIANT 429 429 G -> R (in HANE; type-II). FT /FTId=VAR_007013. FT VARIANT 454 454 V -> E (in HANE; type-II; WE). FT /FTId=VAR_007014. FT VARIANT 456 456 A -> E (in HANE; type-II; MA). FT /FTId=VAR_007015. FT VARIANT 458 458 A -> T (in HANE; type-II; MO). FT /FTId=VAR_007016. FT VARIANT 458 458 A -> V (in HANE; type-II). FT /FTId=VAR_007017. FT VARIANT 465 465 A -> V (in HANE; type-II). FT /FTId=VAR_007018. FT VARIANT 466 466 R -> C (in HANE; type-II; DA). FT /FTId=VAR_007019. FT VARIANT 466 466 R -> H (in HANE; type-II; AT). FT /FTId=VAR_007020. FT VARIANT 466 466 R -> L (in HANE; type-II). FT /FTId=VAR_007021. FT VARIANT 466 466 R -> S (in HANE; type-II). FT /FTId=VAR_007022. FT VARIANT 467 467 T -> P (in HANE; type-II). FT /FTId=VAR_007023. FT VARIANT 473 473 V -> M (in HANE; type-II). FT /FTId=VAR_007024. FT VARIANT 474 474 Q -> E. FT /FTId=VAR_007025. FT VARIANT 477 477 F -> S (in HANE; type-II). FT /FTId=VAR_007026. FT VARIANT 480 480 V -> M (in allele 2; dbSNP:4926). FT /FTId=VAR_007027. FT VARIANT 481 481 L -> P (in HANE; type-II). FT /FTId=VAR_007028. FT VARIANT 481 481 L -> R (in HANE; type-II). FT /FTId=VAR_007029. FT VARIANT 489 489 P -> R (in HANE; type-II). FT /FTId=VAR_007030. FT VARIANT 498 498 P -> S (in HANE; type-II). FT /FTId=VAR_007031. FT CONFLICT 187 187 E -> Q (in Ref. 3). FT CONFLICT 306 306 K -> R (in Ref. 4). FT CONFLICT 314 320 HFKNSVI -> QLQKLSY (in Ref. 10). FT CONFLICT 322 322 V -> M (in Ref. 10). FT CONFLICT 332 332 V -> L (in Ref. 10). FT CONFLICT 370 375 MEQALS -> TGTGSQ (in Ref. 10). FT CONFLICT 417 417 E -> V (in Ref. 10). FT CONFLICT 439 439 S -> F (in Ref. 10). SQ SEQUENCE 500 AA; 55154 MW; 8B5E874833EA6C05 CRC64; MASRLTLLTL LLLLLAGDRA SSNPNATSSS SQDPESLQDR GEGKVATTVI SKMLFVEPIL EVSSLPTTNS TTNSATKITA NTTDEPTTQP TTEPTTQPTI QPTQPTTQLP TDSPTQPTTG SFCPGPVTLC SDLESHSTEA VLGDALVDFS LKLYHAFSAM KKVETNMAFS PFSIASLLTQ VLLGAGENTK TNLESILSYP KDFTCVHQAL KGFTTKGVTS VSQIFHSPDL AIRDTFVNAS RTLYSSSPRV LSNNSDANLE LINTWVAKNT NNKISRLLDS LPSDTRLVLL NAIYLSAKWK TTFDPKKTRM EPFHFKNSVI KVPMMNSKKY PVAHFIDQTL KAKVGQLQLS HNLSLVILVP QNLKHRLEDM EQALSPSVFK AIMEKLEMSK FQPTLLTLPR IKVTTSQDML SIMEKLEFFD FSYDLNLCGL TEDPDLQVSA MQHQTVLELT ETGVEAAAAS AISVARTLLV FEVQQPFLFV LWDQQHKFPV FMGRVYDPRA //