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P05546 (HEP2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 157. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Heparin cofactor 2
Alternative name(s):
Heparin cofactor II
Short name=HC-II
Protease inhibitor leuserpin-2
Short name=HLS2
Serpin D1
Gene names
Name:SERPIND1
Synonyms:HCF2
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length499 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (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. Ref.11

Peptides at the N-terminal of HC-II have chemotactic activity for both monocytes and neutrophils. Ref.11

Tissue specificity

Expressed predominantly in liver. Also present in plasma.

Domain

The N-terminal acidic repeat region mediates, in part, the glycosaminoglycan-accelerated thrombin inhibition. Ref.11

Post-translational modification

Phosphorylation sites are present in the extracellular medium.

Involvement in disease

Thrombophilia due to heparin cofactor 2 deficiency (THPH10) [MIM:612356]: A hemostatic disorder characterized by a tendency to recurrent thrombosis.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.17 Ref.18 Ref.20 Ref.21

Sequence similarities

Belongs to the serpin family.

Sequence caution

The sequence CAG30459.1 differs from that shown. Reason: Erroneous initiation.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 1919 Ref.8
Chain20 – 499480Heparin cofactor 2
PRO_0000032494

Regions

Repeat73 – 83111
Repeat87 – 97112
Region68 – 7912Chemotactic activity
Region73 – 97252 X 11 AA approximate repeats, Asp/Glu-rich (acidic) (hirudin-like)
Region192 – 21221Glycosaminoglycan-binding site

Sites

Site463 – 4642Reactive bond By similarity

Amino acid modifications

Modified residue791Sulfotyrosine Ref.16
Modified residue921Sulfotyrosine Ref.16
Glycosylation491N-linked (GlcNAc...) (complex) Ref.13 Ref.14 Ref.15
Glycosylation1881N-linked (GlcNAc...) Ref.13 Ref.14 Ref.16
Glycosylation3871N-linked (GlcNAc...) Ref.16

Natural variations

Natural variant71A → T. Ref.18
Corresponds to variant rs5905 [ dbSNP | Ensembl ].
VAR_011746
Natural variant601H → P.
Corresponds to variant rs165867 [ dbSNP | Ensembl ].
VAR_011747
Natural variant871S → N.
Corresponds to variant rs34324685 [ dbSNP | Ensembl ].
VAR_051953
Natural variant1291L → V.
Corresponds to variant rs11542069 [ dbSNP | Ensembl ].
VAR_051954
Natural variant2081R → H in THPH10; Oslo; decreased affinity for dermatan sulfate. Ref.17 Ref.18
Corresponds to variant rs5907 [ dbSNP | Ensembl ].
VAR_007112
Natural variant2371K → R.
Corresponds to variant rs1042435 [ dbSNP | Ensembl ].
VAR_011748
Natural variant4421T → M. Ref.18
Corresponds to variant rs5904 [ dbSNP | Ensembl ].
VAR_011749
Natural variant4471E → K in THPH10. Ref.21
VAR_054977
Natural variant4621P → L in THPH10; Tokushima; impaired secretion of the mutant molecules. Ref.20
VAR_054978

Experimental info

Mutagenesis1221R → L: Normal thrombin inhibition and glycosaminoglycan affinity. Ref.12
Mutagenesis1221R → Q: Greatly reduced thrombin inhibition. Normal glycosaminoglycan affinity. Ref.12
Mutagenesis1221R → W: Greatly reduced thrombin inhibition. Normal glycosaminoglycan affinity. Ref.12
Mutagenesis2041K → M: Reduced heparin- and no dermatan sulfate-activated inhibition. Ref.12
Mutagenesis2041K → N: Reduced heparin- and no dermatan sulfate-activated inhibition. Ref.12
Mutagenesis2041K → T: Reduced heparin- and no dermatan sulfate-activated inhibition. Ref.12
Sequence conflict491Missing AA sequence Ref.8
Sequence conflict4831R → P AA sequence Ref.8
Sequence conflict4861C → T AA sequence Ref.8
Sequence conflict4991S → Q AA sequence Ref.8

Secondary structure

....................................................................... 499
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P05546 [UniParc].

Last modified November 1, 1991. Version 3.
Checksum: 3B0E353FE1F6DF05

FASTA49957,071
        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 

« Hide

References

« Hide 'large scale' references
[1]"Heparin cofactor II: cDNA sequence, chromosome localization, restriction fragment length polymorphism, and expression in Escherichia coli."
Blinder M.A., Marasa J.C., Reynolds C.H., Deaven L.L., Tollefsen D.M.
Biochemistry 27:752-759(1988) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]"Complete nucleotide sequence of the gene for human heparin cofactor II and mapping to chromosomal band 22q11."
Herzog R., Lutz S., Blin N., Marasa J.C., Blinder M.A., Tollefsen D.M.
Biochemistry 30:1350-1357(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]"A genome annotation-driven approach to cloning the human ORFeome."
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.
Genome Biol. 5:R84.1-R84.11(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[4]"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. expand/collapse author list , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Liver.
[5]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]"A new member of the plasma protease inhibitor gene family."
Ragg H.
Nucleic Acids Res. 14:1073-1088(1986) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 19-499.
[7]"Isolation and characterization of a partial cDNA clone for heparin cofactor II1."
Inhorn R.C., Tollefsen D.M.
Biochem. Biophys. Res. Commun. 137:431-436(1986) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 333-499.
[8]"Structural evidence for leucine at the reactive site of heparin cofactor II."
Griffith M.J., Noyes C.M., Tyndall J.A., Church F.C.
Biochemistry 24:6777-6782(1985) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 20-52 AND 464-499.
[9]"Structure and expression of the gene coding for the human serpin hLS2."
Ragg H., Preibisch G.
J. Biol. Chem. 263:12129-12134(1988) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-119.
[10]"Leukocyte chemoattractant peptides from the serpin heparin cofactor II."
Church F.C., Pratt C.W., Hoffman M.
J. Biol. Chem. 266:704-709(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 58-85.
[11]"The N-terminal acidic domain of heparin cofactor II mediates the inhibition of alpha-thrombin in the presence of glycosaminoglycans."
van Deerlin V.M.D., Tollefsen D.M.
J. Biol. Chem. 266:20223-20231(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION OF N-TERMINAL ACIDIC DOMAIN.
[12]"Site-directed mutagenesis of arginine 103 and lysine 185 in the proposed glycosaminoglycan-binding site of heparin cofactor II."
Blinder M.A., Tollefsen D.M.
J. Biol. Chem. 265:286-291(1990) [PubMed] [Europe PMC] [Abstract]
Cited for: MUTAGENESIS OF ARG-122 AND LYS-204.
[13]"Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry."
Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J., Smith R.D.
J. Proteome Res. 4:2070-2080(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-49 AND ASN-188.
Tissue: Plasma.
[14]"Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry."
Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.
J. Proteome Res. 8:651-661(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-49 AND ASN-188.
Tissue: Liver.
[15]"A strategy for precise and large scale identification of core fucosylated glycoproteins."
Jia W., Lu Z., Fu Y., Wang H.P., Wang L.H., Chi H., Yuan Z.F., Zheng Z.B., Song L.N., Han H.H., Liang Y.M., Wang J.L., Cai Y., Zhang Y.K., Deng Y.L., Ying W.T., He S.M., Qian X.H.
Mol. Cell. Proteomics 8:913-923(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: GLYCOSYLATION AT ASN-49.
[16]"Crystal structures of native and thrombin-complexed heparin cofactor II reveal a multistep allosteric mechanism."
Baglin T.P., Carrell R.W., Church F.C., Esmon C.T., Huntington J.A.
Proc. Natl. Acad. Sci. U.S.A. 99:11079-11084(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 20-499, GLYCOSYLATION AT ASN-188 AND ASN-387, SULFATION AT TYR-79 AND TYR-92.
[17]"Heparin cofactor IIOslo. Mutation of Arg-189 to His decreases the affinity for dermatan sulfate."
Blinder M.A., Andersson T.R., Abildgaard U., Tollefsen D.M.
J. Biol. Chem. 264:5128-5133(1989) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT THPH10 HIS-208.
[18]"Characterization of single-nucleotide polymorphisms in coding regions of human genes."
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. 22:231-238(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT THPH10 HIS-208, VARIANTS THR-7 AND MET-442.
[19]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)
[20]"Molecular mechanism of type I congenital heparin cofactor (HC) II deficiency caused by a missense mutation at reactive P2 site: HC II Tokushima."
Kanagawa Y., Shigekiyo T., Aihara K., Akaike M., Azuma H., Matsumoto T.
Thromb. Haemost. 85:101-107(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT THPH10 LEU-462, CHARACTERIZATION OF VARIANT THPH10 LEU-462.
[21]"Homozygous deficiency of heparin cofactor II: relevance of P17 glutamate residue in serpins, relationship with conformational diseases, and role in thrombosis."
Corral J., Aznar J., Gonzalez-Conejero R., Villa P., Minano A., Vaya A., Carrell R.W., Huntington J.A., Vicente V.
Circulation 110:1303-1307(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT THPH10 LYS-447.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
M12849 mRNA. Translation: AAA52642.1.
M58600 Genomic DNA. Translation: AAA52641.1.
CR456573 mRNA. Translation: CAG30459.1. Different initiation.
AK314200 mRNA. Translation: BAG36878.1.
CH471176 Genomic DNA. Translation: EAX02941.1.
CH471176 Genomic DNA. Translation: EAX02942.1.
X03498 mRNA. Translation: CAA27218.1.
M33660 Genomic DNA. Translation: AAA36185.1.
CCDSCCDS13783.1.
PIRA37924.
RefSeqNP_000176.2. NM_000185.3.
XP_005261654.1. XM_005261597.1.
UniGeneHs.474270.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1JMJX-ray2.35A/B20-499[»]
1JMOX-ray2.20A20-499[»]
ProteinModelPortalP05546.
SMRP05546. Positions 73-499.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid109303. 3 interactions.
IntActP05546. 5 interactions.
STRING9606.ENSP00000215727.

Chemistry

DrugBankDB00407. Ardeparin.

Protein family/group databases

MEROPSI04.019.

PTM databases

PhosphoSiteP05546.

Polymorphism databases

DMDM123055.

Proteomic databases

MaxQBP05546.
PaxDbP05546.
PRIDEP05546.

Protocols and materials databases

DNASU3053.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000215727; ENSP00000215727; ENSG00000099937.
ENST00000406799; ENSP00000384050; ENSG00000099937.
GeneID3053.
KEGGhsa:3053.
UCSCuc002ztb.1. human.

Organism-specific databases

CTD3053.
GeneCardsGC22P021139.
HGNCHGNC:4838. SERPIND1.
HPACAB008639.
HPA055767.
MIM142360. gene.
612356. phenotype.
neXtProtNX_P05546.
PharmGKBPA35053.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG4826.
HOGENOMHOG000294159.
HOVERGENHBG101242.
InParanoidP05546.
KOK03912.
OMAHIMKLTK.
OrthoDBEOG7327PB.
PhylomeDBP05546.
TreeFamTF343094.

Gene expression databases

BgeeP05546.
CleanExHS_SERPIND1.
GenevestigatorP05546.

Family and domain databases

InterProIPR023795. Serpin_CS.
IPR023796. Serpin_dom.
IPR000215. Serpin_fam.
[Graphical view]
PANTHERPTHR11461. PTHR11461. 1 hit.
PfamPF00079. Serpin. 1 hit.
[Graphical view]
SMARTSM00093. SERPIN. 1 hit.
[Graphical view]
SUPFAMSSF56574. SSF56574. 1 hit.
PROSITEPS00284. SERPIN. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceP05546.
GeneWikiHeparin_cofactor_II.
GenomeRNAi3053.
NextBio12085.
PMAP-CutDBP05546.
PROP05546.
SOURCESearch...

Entry information

Entry nameHEP2_HUMAN
AccessionPrimary (citable) accession number: P05546
Secondary accession number(s): B2RAI1, D3DX34, Q6IBZ5
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1988
Last sequence update: November 1, 1991
Last modified: July 9, 2014
This is version 157 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 22

Human chromosome 22: entries, gene names and cross-references to MIM