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UniProtKB/Swiss-Prot entry P05546


[Entry info] [Name and origin] [References] [Comments] [Cross-references] [Keywords] [Features] [Sequence] [Tools]

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Entry information
Entry name HEP2_HUMAN
Primary accession number P05546
Secondary accession number Q6IBZ5
Integrated into Swiss-Prot on November 1, 1988
Sequence was last modified on November 1, 1991 (Sequence version 3)
Annotations were last modified on    November 4, 2008 (Entry version 101)
Name and origin of the protein
Protein name Heparin cofactor 2 [Precursor]
Synonyms Heparin cofactor II
HC-II
Protease inhibitor leuserpin 2
HLS2
Gene name
Name: SERPIND1
Synonyms: HCF2
From
Homo sapiens (Human) [TaxID: 9606] 
Taxonomy Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.
Protein existence 1: Evidence at protein level;
References
[1]
NUCLEOTIDE SEQUENCE [MRNA].
DOI=10.1021/bi00402a039; PubMed=2894851 [NCBI, ExPASy, EBI, Israel, Japan]
Blinder M.A., Marasa J.C., Reynolds C.H., Deaven L.L., Tollefsen D.M.;
"Heparin cofactor II: cDNA sequence, chromosome localization, restriction fragment length polymorphism, and expression in Escherichia coli.";
Biochemistry 27:752-759(1988).
[2]
NUCLEOTIDE SEQUENCE [GENOMIC DNA].
DOI=10.1021/bi00219a027; PubMed=1671335 [NCBI, ExPASy, EBI, Israel, Japan]
Herzog R., Lutz S., Blin N., Marasa J.C., Blinder M.A., Tollefsen D.M.;
"Complete nucleotide sequence of the gene for human heparin cofactor II and mapping to chromosomal band 22q11.";
Biochemistry 30:1350-1357(1991).
[3]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
DOI=10.1186/gb-2004-5-10-r84; PubMed=15461802 [NCBI, ExPASy, EBI, Israel, Japan]
Collins J.E., Wright C.L., Edwards C.A., Davis M.P., Grinham J.A., Cole C.G., Goward M.E., Aguado B., Mallya M., Mokrab Y., Huckle E.J., Beare D.M., Dunham I.;
"A genome annotation-driven approach to cloning the human ORFeome.";
Genome Biol. 5:RESEARCH84.1-RESEARCH84.11(2004).
[4]
NUCLEOTIDE SEQUENCE [MRNA] OF 19-499.
DOI=10.1093/nar/14.2.1073; PubMed=3003690 [NCBI, ExPASy, EBI, Israel, Japan]
Ragg H.;
"A new member of the plasma protease inhibitor gene family.";
Nucleic Acids Res. 14:1073-1088(1986).
[5]
NUCLEOTIDE SEQUENCE [MRNA] OF 333-499.
DOI=10.1016/0006-291X(86)91228-3; PubMed=3755044 [NCBI, ExPASy, EBI, Israel, Japan]
Inhorn R.C., Tollefsen D.M.;
"Isolation and characterization of a partial cDNA clone for heparin cofactor II1.";
Biochem. Biophys. Res. Commun. 137:431-436(1986).
[6]
PROTEIN SEQUENCE OF 20-52 AND 464-499.
DOI=10.1021/bi00345a008; PubMed=3907702 [NCBI, ExPASy, EBI, Israel, Japan]
Griffith M.J., Noyes C.M., Tyndall J.A., Church F.C.;
"Structural evidence for leucine at the reactive site of heparin cofactor II.";
Biochemistry 24:6777-6782(1985).
[7]
NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-119.
PubMed=2841345 [NCBI, ExPASy, EBI, Israel, Japan]
Ragg H., Preibisch G.;
"Structure and expression of the gene coding for the human serpin hLS2.";
J. Biol. Chem. 263:12129-12134(1988).
[8]
PROTEIN SEQUENCE OF 58-85.
PubMed=1985958 [NCBI, ExPASy, EBI, Israel, Japan]
Church F.C., Pratt C.W., Hoffman M.;
"Leukocyte chemoattractant peptides from the serpin heparin cofactor II.";
J. Biol. Chem. 266:704-709(1991).
[9]
FUNCTION OF N-TERMINAL ACIDIC DOMAIN.
PubMed=1939083 [NCBI, ExPASy, EBI, Israel, Japan]
van Deerlin V.M.D., Tollefsen D.M.;
"The N-terminal acidic domain of heparin cofactor II mediates the inhibition of alpha-thrombin in the presence of glycosaminoglycans.";
J. Biol. Chem. 266:20223-20231(1991).
[10]
MUTAGENESIS OF ARG-122 AND LYS-204.
PubMed=2104620 [NCBI, ExPASy, EBI, Israel, Japan]
Blinder M.A., Tollefsen D.M.;
"Site-directed mutagenesis of arginine 103 and lysine 185 in the proposed glycosaminoglycan-binding site of heparin cofactor II.";
J. Biol. Chem. 265:286-291(1990).
[11]
GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-49 AND ASN-188, AND MASS SPECTROMETRY.
TISSUE=Plasma;
DOI=10.1021/pr0502065; PubMed=16335952 [NCBI, ExPASy, EBI, Israel, Japan]
Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J., Smith R.D.;
"Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry.";
J. Proteome Res. 4:2070-2080(2005).
[12]
VARIANT HCF-II DEFICIENCY HIS-208.
PubMed=2647747 [NCBI, ExPASy, EBI, Israel, Japan]
Blinder M.A., Andersson T.R., Abildgaard U., Tollefsen D.M.;
"Heparin cofactor IIOslo. Mutation of Arg-189 to His decreases the affinity for dermatan sulfate.";
J. Biol. Chem. 264:5128-5133(1989).
[13]
VARIANT HCF-II DEFICIENCY HIS-208, AND VARIANTS THR-7 AND MET-442.
DOI=10.1038/10290; PubMed=10391209 [NCBI, ExPASy, EBI, Israel, Japan]
Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L., Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q., Lander E.S.;
"Characterization of single-nucleotide polymorphisms in coding regions of human genes.";
Nat. Genet. 22:231-238(1999).
[14]
ERRATUM.
Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L., Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q., Lander E.S.;
Nat. Genet. 23:373-373(1999).
Comments
  • FUNCTION: Thrombin inhibitor activated by the glycosaminoglycans, heparin or dermatan sulfate. In the presence of the latter, HC-II becomes the predominant thrombin inhibitor in place of antithrombin III (AT-III). Also inhibits chymotrypsin, but in a glycosaminoglycan-independent manner.
  • FUNCTION: Peptides at the N-terminal of HC-II have chemotactic activity for both monocytes and neutrophils.
  • TISSUE SPECIFICITY: Expressed predominantly in liver.
  • DOMAIN: The N-terminal acidic repeat region mediates, in part, the glycosaminoglycan-accelerated thrombin inhibition.
  • DISEASE: Defects in SERPIND1 are the cause of heparin cofactor II deficiency (HCF-II deficiency) [MIM:142360]. HCF-II deficiency is an important risk factor for hereditary thrombophilia [MIM:188050], a multifactorial trait characterized by recurrent thrombosis and abnormal platelet aggregation in response to various agents. HCF-II deficiency is inherited as an autosomal dominant disorder, in which affected individuals are prone to develop serious spontaneous thrombosis.
  • SIMILARITY: Belongs to the serpin family.
Copyright
Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms. Distributed under the Creative Commons Attribution-NoDerivs License.
Cross-references
Sequence databases
EMBL
M12849; AAA52642.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M58600; AAA52641.1; -; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
CR456573; CAG30459.1; ALT_INIT; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
X03498; CAA27218.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M33660; AAA36185.1; -; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
PIR A37924; A37924.
RefSeq NP_000176.2; -.
UniGene Hs.474270
3D structure databases
PDB
1JMJ; X-ray; 2.35 A; A/B=20-499.[ExPASy / RCSB / EBI]
1JMO; X-ray; 2.20 A; A=20-499.[ExPASy / RCSB / EBI]
Detailed list of linked structures.
PDBsum 1JMJ; -.
1JMO; -.
ModBase P05546.
Protein family/group databases
MEROPS I04.019; -.
Organism-specific databases
H-InvDB HIX0027857; -.
HGNC HGNC:4838; SERPIND1.
GenAtlas SERPIND1.
HPA CAB008639; -.
MIM 142360; gene+phenotype. [NCBI / EBI]
188050; phenotype. [NCBI / EBI]
PharmGKB PA35053; -.
GeneCards P05546.
Gene expression databases
ArrayExpress P05546; -.
CleanEx HS_SERPIND1; -.
GermOnline ENSG00000099937; Homo sapiens.
Ontologies
GO
GO:0005576; Cellular component: extracellular region (non-traceable author statement from UniProtKB).
GO:0004866; Molecular function: endopeptidase inhibitor activity (traceable author statement from ProtInc).
QuickGo view.
Family and domain databases
InterPro IPR000295; Prot_inh_Lserp2.
IPR000215; Protease_inhib_I4_serpin.
Graphical view of domain structure.
PANTHER PTHR11461; Prot_inh_serpin; 1.
Pfam PF00079; Serpin; 1.
Pfam graphical view of domain structure.
PRINTS PR00780; LEUSERPINII.
SMART SM00093; SERPIN; 1.
SMART graphical view of domain structure.
PROSITE PS00284; SERPIN; 1.
BLOCKS P05546.
ProtoNet P05546.
Genome annotation databases
Ensembl ENSG00000099937; Homo sapiens. [Contig view]
GeneID 3053; -.
KEGG hsa:3053; -.
NMPDR fig|9606.3.peg.21291; -.
Phylogenomic databases
HOGENOM P05546; -.
HOVERGEN P05546; -.
Other
DrugBank DB00407; Ardeparin.
LinkHub P05546; -.
NextBio 12085; -.
SOURCE SERPIND1; Homo sapiens.
UniRef View cluster of proteins with at least 50% / 90% / 100% identity.
Keywords
3D-structure; Blood coagulation; Chemotaxis; Direct protein sequencing; Disease mutation; Glycoprotein; Heparin-binding; Polymorphism; Protease inhibitor; Repeat; Serine protease inhibitor; Signal; Sulfation; Thrombophilia.
Features
SEVIEWER logo Feature table viewer FT aligner logo Feature aligner
KeyFrom   To Length Description FTId
SIGNAL   1    19  19      
CHAIN   20   499  480     Heparin cofactor 2. PRO_0000032494
REPEAT   73    83  11     1. 
REPEAT   87    97  11     2. 
REGION   68    79  12     Chemotactic activity. 
REGION   73    97  25     2 X 11 AA approximate repeats, Asp/Glu-rich (acidic) (hirudin-like). 
REGION   192   212  21     Glycosaminoglycan-binding site. 
SITE   463   464  2     Reactive bond (By similarity). 
MOD_RES   79    79        Sulfotyrosine. 
MOD_RES   92    92        Sulfotyrosine. 
CARBOHYD   49    49        N-linked (GlcNAc...). 
CARBOHYD   188   188        N-linked (GlcNAc...). 
CARBOHYD   387   387        N-linked (GlcNAc...) (Potential). 
VARIANT   7     7  1     A -> T (in dbSNP:rs5905 [NCBI]). VAR_011746 
VARIANT   60    60  1     H -> P (in dbSNP:rs165867 [NCBI]). VAR_011747 
VARIANT   208   208  1     R -> H (in HCF-II deficiency; Oslo; decreased affinity for dermatan sulfate; dbSNP:rs6065 [NCBI]). VAR_007112 [3D]
VARIANT   237   237  1     K -> R (in dbSNP:rs1042435 [NCBI]). VAR_011748 [3D]
VARIANT   442   442  1     T -> M (in dbSNP:rs5904 [NCBI]). VAR_011749 [3D]
MUTAGEN   122   122        R->L: Normal thrombin inhibition and glycosaminoglycan affinity. 
MUTAGEN   122   122        R->Q: Greatly reduced thrombin inhibition. Normal glycosaminoglycan affinity. 
MUTAGEN   122   122        R->W: Greatly reduced thrombin inhibition. Normal glycosaminoglycan affinity. 
MUTAGEN   204   204        K->M: Reduced heparin- and no dermatan sulfate-activated inhibition. 
MUTAGEN   204   204        K->N: Reduced heparin- and no dermatan sulfate-activated inhibition. 
MUTAGEN   204   204        K->T: Reduced heparin- and no dermatan sulfate-activated inhibition. 
CONFLICT   49    49        Missing (in Ref. 6; AA sequence). 
CONFLICT   483   483        R -> P (in Ref. 6; AA sequence). 
CONFLICT   486   486        C -> T (in Ref. 6; AA sequence). 
CONFLICT   499   499        S -> Q (in Ref. 6; AA sequence). 
HELIX   82    86  5      
HELIX   122   142  21      
STRAND   151   153  3      
HELIX   155   165  11      
HELIX   166   168  3      
HELIX   171   180  10      
HELIX   183   189  7      
HELIX   195   210  16      
STRAND   214   227  14      
HELIX   234   243  10      
STRAND   248   251  4      
HELIX   256   269  14      
TURN   270   272  3      
TURN   277   280  4      
STRAND   287   301  15      
HELIX   305   307  3      
STRAND   309   316  8      
STRAND   319   337  19      
TURN   338   341  4      
STRAND   342   349  8      
TURN   350   352  3      
STRAND   353   362  10      
HELIX   365   372  8      
HELIX   375   383  9      
STRAND   386   395  10      
STRAND   397   404  8      
HELIX   406   412  7      
HELIX   416   418  3      
TURN   425   427  3      
STRAND   435   445  11      
STRAND   447   451  5      
STRAND   466   470  5      
STRAND   475   481  7      
TURN   482   485  4      
STRAND   486   494  9      
Sequence information
Length: 499 AA [This is the length of the unprocessed precursor] Molecular weight: 57071 Da [This is the MW of the unprocessed precursor] CRC64: 3B0E353FE1F6DF05 [This is a checksum on the sequence]
        10         20         30         40         50         60 
MKHSLNALLI FLIITSAWGG SKGPLDQLEK GGETAQSADP QWEQLNNKNL SMPLLPADFH 

        70         80         90        100        110        120 
KENTVTNDWI PEGEEDDDYL DLEKIFSEDD DYIDIVDSLS VSPTDSDVSA GNILQLFHGK 

       130        140        150        160        170        180 
SRIQRLNILN AKFAFNLYRV LKDQVNTFDN IFIAPVGIST AMGMISLGLK GETHEQVHSI 

       190        200        210        220        230        240 
LHFKDFVNAS SKYEITTIHN LFRKLTHRLF RRNFGYTLRS VNDLYIQKQF PILLDFKTKV 

       250        260        270        280        290        300 
REYYFAEAQI ADFSDPAFIS KTNNHIMKLT KGLIKDALEN IDPATQMMIL NCIYFKGSWV 

       310        320        330        340        350        360 
NKFPVEMTHN HNFRLNEREV VKVSMMQTKG NFLAANDQEL DCDILQLEYV GGISMLIVVP 

       370        380        390        400        410        420 
HKMSGMKTLE AQLTPRVVER WQKSMTNRTR EVLLPKFKLE KNYNLVESLK LMGIRMLFDK 

       430        440        450        460        470        480 
NGNMAGISDQ RIAIDLFKHQ GTITVNEEGT QATTVTTVGF MPLSTQVRFT VDRPFLFLIY 

       490 
EHRTSCLLFM GRVANPSRS 

P05546 in FASTA format

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