Reviewed, UniProtKB/Swiss-Prot P05546 (HEP2_HUMAN)

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

Gene names

Name:	SERPIND1
Synonyms:	HCF2

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › 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.9 Peptides at the N-terminal of HC-II have chemotactic activity for both monocytes and neutrophils. Ref.9
Tissue specificity	Expressed predominantly in liver.
Domain	The N-terminal acidic repeat region mediates, in part, the glycosaminoglycan-accelerated thrombin inhibition. Ref.9
Involvement in disease	Defects in SERPIND1 are the cause of heparin cofactor 2 deficiency (HCF2D) [MIM:612356]. HCF2D is an important risk factor for hereditary thrombophilia, a hemostatic disorder characterized by a tendency to recurrent thrombosis. Ref.13 Ref.14 Ref.16 Ref.17
Sequence similarities	Belongs to the serpin family.

Ontologies

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

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 19

19

Ref.6

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

Modified residue

92

1

Sulfotyrosine

Glycosylation

49

1

N-linked (GlcNAc...) Ref.11

Glycosylation

188

1

N-linked (GlcNAc...) Ref.11

Glycosylation

387

1

N-linked (GlcNAc...) Potential

Natural variations

Natural variant

7

1

A → T: dbSNP rs5905. Ref.14

VAR_011746

Natural variant

60

1

H → P: dbSNP rs165867.

VAR_011747

Natural variant

87

1

S → N: dbSNP rs34324685.

VAR_051953

Natural variant

129

1

L → V: dbSNP rs11542069.

VAR_051954

Natural variant

208

1

R → H in HCF2D; Oslo; decreased affinity for dermatan sulfate. dbSNP rs5907. Ref.13 Ref.14

VAR_007112

Natural variant

237

1

K → R: dbSNP rs1042435.

VAR_011748

Natural variant

442

1

T → M: dbSNP rs5904. Ref.14

VAR_011749

Natural variant

447

1

E → K in HCF2D. Ref.17

VAR_054977

Natural variant

462

1

P → L in HCF2D; Tokushima; impaired secretion of the mutant molecules. Ref.16

VAR_054978

Experimental info

Mutagenesis

122

1

R → L: Normal thrombin inhibition and glycosaminoglycan affinity. Ref.10

Mutagenesis

122

1

R → Q: Greatly reduced thrombin inhibition. Normal glycosaminoglycan affinity. Ref.10

Mutagenesis

122

1

R → W: Greatly reduced thrombin inhibition. Normal glycosaminoglycan affinity. Ref.10

Mutagenesis

204

1

K → M: Reduced heparin- and no dermatan sulfate-activated inhibition. Ref.10

Mutagenesis

204

1

K → N: Reduced heparin- and no dermatan sulfate-activated inhibition. Ref.10

Mutagenesis

204

1

K → T: Reduced heparin- and no dermatan sulfate-activated inhibition. Ref.10

Sequence conflict

49

1

Missing AA sequence Ref.6

Sequence conflict

483

1

R → P AA sequence Ref.6

Sequence conflict

486

1

C → T AA sequence Ref.6

Sequence conflict

499

1

S → Q AA sequence Ref.6

Secondary structure

1

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499

Helix Strand Turn

Details...

Helix

82 – 86

5

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 – 243

10

Beta strand

248 – 251

4

Helix

256 – 269

14

Turn

270 – 272

3

Turn

277 – 280

4

Beta strand

287 – 301

15

Helix

305 – 307

3

Beta strand

309 – 316

8

Beta strand

319 – 337

19

Turn

338 – 341

4

Beta strand

342 – 349

8

Turn

350 – 352

3

Beta strand

353 – 362

10

Helix

365 – 372

8

Helix

375 – 383

9

Beta strand

386 – 395

10

Beta strand

397 – 404

8

Helix

406 – 412

7

Helix

416 – 418

3

Turn

425 – 427

3

Beta strand

435 – 445

11

Beta strand

447 – 451

5

Beta strand

466 – 470

5

Beta strand

475 – 481

7

Turn

482 – 485

4

Beta strand

486 – 494

9

Sequences

	Sequence		Length	Mass (Da)
	P05546-1 [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: 2894851] [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: 1671335] [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:RESEARCH84.1-RESEARCH84.11(2004) [PubMed: 15461802] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[4]	"A new member of the plasma protease inhibitor gene family." Ragg H. Nucleic Acids Res. 14:1073-1088(1986) [PubMed: 3003690] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 19-499.
[5]	"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: 3755044] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 333-499.
[6]	"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: 3907702] [Abstract] Cited for: PROTEIN SEQUENCE OF 20-52 AND 464-499.
[7]	"Structure and expression of the gene coding for the human serpin hLS2." Ragg H., Preibisch G. J. Biol. Chem. 263:12129-12134(1988) [PubMed: 2841345] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-119.
[8]	"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: 1985958] [Abstract] Cited for: PROTEIN SEQUENCE OF 58-85.
[9]	"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: 1939083] [Abstract] Cited for: FUNCTION OF N-TERMINAL ACIDIC DOMAIN.
[10]	"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: 2104620] [Abstract] Cited for: MUTAGENESIS OF ARG-122 AND LYS-204.
[11]	"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: 16335952] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-49 AND ASN-188, MASS SPECTROMETRY. Tissue: Plasma.
[12]	"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: 19159218] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-49 AND ASN-188, MASS SPECTROMETRY. Tissue: Liver.
[13]	"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: 2647747] [Abstract] Cited for: VARIANT HCF2D HIS-208.
[14]	"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: 10391209] [Abstract] Cited for: VARIANT HCF2D HIS-208, VARIANTS THR-7 AND MET-442.
[15]	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)
[16]	"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: 11204559] [Abstract] Cited for: VARIANT HCF2D LEU-462, CHARACTERIZATION OF VARIANT HCF2D LEU-462.
[17]	"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: 15337701] [Abstract] Cited for: VARIANT HCF2D LYS-447.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBLGenBankDDBJ

M12849 mRNA. Translation: AAA52642.1.
M58600 Genomic DNA. Translation: AAA52641.1.
CR456573 mRNA. Translation: CAG30459.1. Different initiation.
X03498 mRNA. Translation: CAA27218.1.
M33660 Genomic DNA. Translation: AAA36185.1.

IPI

IPI00879573.

PIR

A37924.

RefSeq

NP_000176.2.

UniGene

Hs.474270

3D structure databases

PDBPDBe

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

ModBase

Search...

Protein family/group databases

MEROPS

I04.019.

Proteomic databases

PRIDE

P05546.

Genome annotation databases

Ensembl

ENSG00000099937. Homo sapiens. [Contig view]

GeneID

3053.

KEGG

hsa:3053.

NMPDR

fig|9606.3.peg.21291.

UCSC

uc002ztb.1. human.

Organism-specific databases

GeneCards

GC22P019452.

H-InvDB

HIX0027857.

HGNC

HGNC:4838. SERPIND1.

HPA

CAB008639.

MIM

142360. gene.
188050. phenotype.
612356. phenotype.

PharmGKB

PA35053.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P05546.

HOVERGEN

P05546.

OMA

P05546. IQRLNIL.

Gene expression databases

ArrayExpress

P05546.

Bgee

P05546.

CleanEx

HS_SERPIND1.

GermOnline

ENSG00000099937. Homo sapiens.

Family and domain databases

InterPro

IPR000295. Prot_inh_Lserp2.
IPR000215. Protease_inhib_I4_serpin.
[Graphical view]

PANTHER

PTHR11461. Prot_inh_serpin. 1 hit.

Pfam

PF00079. Serpin. 1 hit.
[Graphical view]

PRINTS

PR00780. LEUSERPINII.

SMART

SM00093. SERPIN. 1 hit.
[Graphical view]

PROSITE

PS00284. SERPIN. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

DrugBank

DB00407. Ardeparin.

NextBio

12085.

PMAP-CutDB

P05546.

SOURCE

Search...

Entry information

Entry name

HEP2_HUMAN

Accession

Primary (citable) accession number: P05546
Secondary accession number(s): Q6IBZ5

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1988
Last sequence update:	November 1, 1991
Last modified:	July 7, 2009
This is version 109 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)