P05546 (HEP2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	499 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence 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.16 Ref.17 Ref.19 Ref.20
Sequence similarities	Belongs to the serpin family.
Sequence caution	The sequence CAG30459.1 differs from that shown. Reason: Erroneous initiation.

Ontologies

Keywords
Biological process	Blood coagulation Chemotaxis Hemostasis
Coding sequence diversity	Polymorphism
Disease	Disease mutation Thrombophilia
Domain	Repeat Signal
Ligand	Heparin-binding
Molecular function	Protease inhibitor Serine protease inhibitor
PTM	Glycoprotein Phosphoprotein Sulfation
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	blood coagulation Inferred from electronic annotation. Source: UniProtKB-KW chemotaxis Inferred from electronic annotation. Source: UniProtKB-KW regulation of proteolysis Inferred from Biological aspect of Ancestor. Source: RefGenome
Cellular_component	extracellular region Non-traceable author statement PubMed 14718574. Source: UniProtKB
Molecular_function	heparin binding Inferred from electronic annotation. Source: UniProtKB-KW serine-type endopeptidase inhibitor activity Inferred from Biological aspect of Ancestor. Source: RefGenome
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 19

19

Ref.8

Chain

20 – 499

480

Heparin cofactor 2

PRO_0000032494

Regions

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

Sites

Site

463 – 464

2

Reactive bond By similarity

Amino acid modifications

Modified residue

79

1

Sulfotyrosine Ref.15

Modified residue

92

1

Sulfotyrosine Ref.15

Glycosylation

49

1

N-linked (GlcNAc...) Ref.13 Ref.14

Glycosylation

188

1

N-linked (GlcNAc...) Ref.13 Ref.14 Ref.15

Glycosylation

387

1

N-linked (GlcNAc...) Ref.15

Natural variations

Natural variant

7

1

A → T. Ref.17
Corresponds to variant rs5905 [ dbSNP | Ensembl ].

VAR_011746

Natural variant

60

1

H → P.
Corresponds to variant rs165867 [ dbSNP | Ensembl ].

VAR_011747

Natural variant

87

1

S → N.
Corresponds to variant rs34324685 [ dbSNP | Ensembl ].

VAR_051953

Natural variant

129

1

L → V.
Corresponds to variant rs11542069 [ dbSNP | Ensembl ].

VAR_051954

Natural variant

208

1

R → H in THPH10; Oslo; decreased affinity for dermatan sulfate. Ref.16 Ref.17
Corresponds to variant rs5907 [ dbSNP | Ensembl ].

VAR_007112

Natural variant

237

1

K → R.
Corresponds to variant rs1042435 [ dbSNP | Ensembl ].

VAR_011748

Natural variant

442

1

T → M. Ref.17
Corresponds to variant rs5904 [ dbSNP | Ensembl ].

VAR_011749

Natural variant

447

1

E → K in THPH10. Ref.20

VAR_054977

Natural variant

462

1

P → L in THPH10; Tokushima; impaired secretion of the mutant molecules. Ref.19

VAR_054978

Experimental info

Mutagenesis

122

1

R → L: Normal thrombin inhibition and glycosaminoglycan affinity. Ref.12

Mutagenesis

122

1

R → Q: Greatly reduced thrombin inhibition. Normal glycosaminoglycan affinity. Ref.12

Mutagenesis

122

1

R → W: Greatly reduced thrombin inhibition. Normal glycosaminoglycan affinity. Ref.12

Mutagenesis

204

1

K → M: Reduced heparin- and no dermatan sulfate-activated inhibition. Ref.12

Mutagenesis

204

1

K → N: Reduced heparin- and no dermatan sulfate-activated inhibition. Ref.12

Mutagenesis

204

1

K → T: Reduced heparin- and no dermatan sulfate-activated inhibition. Ref.12

Sequence conflict

49

1

Missing AA sequence Ref.8

Sequence conflict

483

1

R → P AA sequence Ref.8

Sequence conflict

486

1

C → T AA sequence Ref.8

Sequence conflict

499

1

S → Q AA sequence Ref.8

Secondary structure

1

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499

Helix Strand Turn

Details...

Helix

82 – 87

6

Helix

90 – 92

3

Helix

122 – 142

21

Beta strand

151 – 153

3

Helix

155 – 165

11

Helix

166 – 168

3

Helix

171 – 180

10

Helix

183 – 189

7

Helix

195 – 210

16

Beta strand

214 – 227

14

Helix

234 – 244

11

Beta strand

248 – 251

4

Helix

256 – 269

14

Turn

270 – 272

3

Turn

277 – 280

4

Beta strand

287 – 296

10

Beta strand

299 – 301

3

Helix

305 – 307

3

Beta strand

309 – 314

6

Beta strand

316 – 318

3

Beta strand

320 – 337

18

Turn

338 – 341

4

Beta strand

342 – 349

8

Turn

350 – 352

3

Beta strand

353 – 362

10

Helix

363 – 365

3

Helix

366 – 372

7

Helix

375 – 384

10

Beta strand

386 – 395

10

Beta strand

397 – 400

4

Helix

406 – 412

7

Helix

416 – 418

3

Turn

425 – 427

3

Beta strand

434 – 445

12

Beta strand

447 – 451

5

Beta strand

459 – 462

4

Beta strand

468 – 470

3

Beta strand

475 – 481

7

Turn

482 – 485

4

Beta strand

486 – 494

9

Sequences

	Sequence		Length	Mass (Da)
	P05546 [UniParc]. Last modified November 1, 1991. Version 3. Checksum: 3B0E353FE1F6DF05	FASTA	499	57,071
	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

References

	« Hide 'large scale' referencesShow '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. , 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. , 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, MASS SPECTROMETRY. 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, MASS SPECTROMETRY. Tissue: Liver.
[15]	"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.
[16]	"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.
[17]	"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.
[18]	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)
[19]	"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.
[20]	"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.

IPI

IPI00879573.

PIR

A37924.

RefSeq

NP_000176.2. NM_000185.3.

UniGene

Hs.474270.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1JMJ	X-ray	2.35	A/B	20-499	[»]
1JMO	X-ray	2.20	A	20-499	[»]

ProteinModelPortal

P05546.

ModBase

Search...

Protein-protein interaction databases

IntAct

P05546. 3 interactions.

STRING

9606.ENSP00000215727.

Protein family/group databases

MEROPS

I04.019.

PTM databases

PhosphoSite

P05546.

Polymorphism databases

DMDM

123055.

Proteomic databases

PaxDb

P05546.

PRIDE

P05546.

Protocols and materials databases

DNASU

3053.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000215727; ENSP00000215727; ENSG00000099937.
ENST00000406799; ENSP00000384050; ENSG00000099937.

GeneID

3053.

KEGG

hsa:3053.

UCSC

uc002ztb.1. human.

Organism-specific databases

CTD

3053.

GeneCards

GC22P021139.

HGNC

HGNC:4838. SERPIND1.

HPA

CAB008639.

MIM

142360. gene.
612356. phenotype.

neXtProt

NX_P05546.

PharmGKB

PA35053.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG4826.

HOGENOM

HOG000294159.

HOVERGEN

HBG101242.

InParanoid

P05546.

KO

K03912.

OMA

CIYFKGT.

OrthoDB

EOG4RV2R5.

PhylomeDB

P05546.

Gene expression databases

Bgee

P05546.

CleanEx

HS_SERPIND1.

Genevestigator

P05546.

GermOnline

ENSG00000099937. Homo sapiens.

Family and domain databases

InterPro

IPR000295. Prot_inh_Lserp2.
IPR023795. Protease_inhib_I4_serpin_CS.
IPR023796. Serpin_dom.
IPR000215. Serpin_fam.
[Graphical view]

PANTHER

PTHR11461. PTHR11461. 1 hit.

Pfam

PF00079. Serpin. 1 hit.
[Graphical view]

PRINTS

PR00780. LEUSERPINII.

SMART

SM00093. SERPIN. 1 hit.
[Graphical view]

SUPFAM

SSF56574. Prot_inh_serpin. 1 hit.

PROSITE

PS00284. SERPIN. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

DrugBank

DB00407. Ardeparin.

EvolutionaryTrace

P05546.

GenomeRNAi

3053.

NextBio

12085.

PMAP-CutDB

P05546.

SOURCE

Search...

Entry information

Entry name

HEP2_HUMAN

Accession

Primary (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:	May 1, 2013
This is version 146 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.