P35052 (GPC1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Glypican-1

Cleaved into the following chain:

1. Secreted glypican-1

Gene names

Name:

GPC1

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	558 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	Cell surface proteoglycan that bears heparan sulfate. Binds, via the heparan sulfate side chains, alpha-4 (V) collagen and participates in Schwann cell myelination By similarity. May act as a catalyst in increasing the rate of conversion of prion protein PRPN(C) to PRNP(Sc) via associating (via the heparan sulfate side chains) with both forms of PRPN, targeting them to lipid rafts and facilitating their interaction. Required for proper skeletal muscle differentiation by sequestering FGF2 in lipid rafts preventing its binding to receptors (FGFRs) and inhibiting the FGF-mediated signaling. Ref.10 Ref.12
Subcellular location	Cell membrane; Lipid-anchor › GPI-anchor; Extracellular side. Endosome. Note: S-nitrosylated form recycled in endosomes. Localizes to CAV1-containing vesicles close to the cell surface. Cleavage of heparan sulfate side chains takes place mainly in late endosomes. Associates with both forms of PRNP in lipid rafts. Colocalizes with APP in perinuclear compartments and with CP in intracellular compartments. Associates with fibrillar APP Abeta peptides in lipid rafts in Alzheimer disease brains. Ref.1 Ref.5 Ref.7 Ref.9 Ref.10 Secreted glypican-1: Secreted › extracellular space Ref.5 Ref.7 Ref.9 Ref.10.
Post-translational modification	S-nitrosylated in a Cu2+-dependent manner. Nitric acid (NO) is released from the nitrosylated cysteines by ascorbate or by some other reducing agent, in a Cu2+ or Zn2+ dependent manner. This free nitric oxide is then capable of cleaving the heparan sulfate side chains. N- and O-glycosylated. N-glycosylation is mainly of the complex type containing sialic acid. O-glycosylated with heparan sulfate. The heparan sulfate chains can be cleaved either by the action of heparanase or, degraded by a daaminative process that uses nitric oxide (NO) released from the S-nitrosylated cysteines. This process is triggered by ascorbate, or by some other reducing agent, in a Cu2+- or Zn2+ dependent manner. Cu2+ ions are provided by ceruloproteins such as APP, PRNP or CP which associate with GCP1 in intracellular compartments or lipid rafts. Ref.1 Ref.4 Ref.7 Ref.8 Ref.9 Ref.11 Ref.12 Ref.13 This cell-associated glypican is further processed to give rise to a medium-released species.
Involvement in disease	Associates (via the heparan sulfate side chains) with fibrillar APP-beta amyloid peptides in primitive and classic amyloid plaques and may be involved in the deposition of these senile plaques in the Alzheimer disease (AD) brain. Ref.5 Ref.6 Misprocessing of GPC1 is found in fibroblasts of patients with Niemann-Pick Type C1 disease. This is due to the defective deaminative degradation of heparan sulfate chains. Ref.5 Ref.6
Sequence similarities	Belongs to the glypican family.

Ontologies

Keywords
Cellular component	Cell membrane Endosome Membrane Secreted
Coding sequence diversity	Polymorphism
Domain	Signal
Ligand	Copper Zinc
PTM	Disulfide bond GPI-anchor Glycoprotein Heparan sulfate Lipoprotein Proteoglycan S-nitrosylation
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	Schwann cell differentiation Inferred from sequence or structural similarity. Source: UniProtKB axon guidance Traceable author statement. Source: Reactome carbohydrate metabolic process Traceable author statement. Source: Reactome chondroitin sulfate metabolic process Traceable author statement. Source: Reactome glycosaminoglycan biosynthetic process Traceable author statement. Source: Reactome glycosaminoglycan catabolic process Traceable author statement. Source: Reactome heparan sulfate proteoglycan catabolic process Inferred from direct assay Ref.4. Source: UniProtKB myelin assembly Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of fibroblast growth factor receptor signaling pathway Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of skeletal muscle cell differentiation Inferred from sequence or structural similarity. Source: UniProtKB
Cellular_component	Golgi lumen Traceable author statement. Source: Reactome anchored to membrane Inferred from electronic annotation. Source: UniProtKB-KW endosome Inferred from electronic annotation. Source: UniProtKB-SubCell extracellular space Traceable author statement Ref.1. Source: ProtInc integral to plasma membrane Traceable author statement Ref.1. Source: ProtInc lysosomal lumen Traceable author statement. Source: Reactome membrane raft Inferred from sequence or structural similarity. Source: UniProtKB proteinaceous extracellular matrix Inferred from sequence or structural similarity. Source: UniProtKB
Molecular_function	copper ion binding Inferred from direct assay Ref.4. Source: UniProtKB fibroblast growth factor binding Inferred from sequence or structural similarity. Source: UniProtKB laminin binding Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 23

23

Ref.1

Chain

24 – 530

507

Glypican-1

PRO_0000012295

Chain

24 – ?

Secreted glypican-1

PRO_0000333837

Propeptide

531 – 558

28

Removed in mature form Probable

PRO_0000012296

Amino acid modifications

Lipidation

530

1

GPI-anchor amidated serine Probable

Glycosylation

79

1

N-linked (GlcNAc...) Ref.11 Ref.13

Glycosylation

116

1

N-linked (GlcNAc...) Ref.1 Ref.11 Ref.13

Glycosylation

486

1

O-linked (Xyl...) (heparan sulfate) Probable

Glycosylation

488

1

O-linked (Xyl...) (heparan sulfate) Probable

Glycosylation

490

1

O-linked (Xyl...) (heparan sulfate) Probable

Disulfide bond

32 ↔ 68

Ref.13

Disulfide bond

62 ↔ 256

Ref.13

Disulfide bond

69 ↔ 259

Ref.13

Disulfide bond

191 ↔ 343

Ref.13

Disulfide bond

246 ↔ 279

Ref.13

Disulfide bond

268 ↔ 415

Ref.13

Disulfide bond

272 ↔ 401

Ref.13

Natural variations

Natural variant

337

1

A → D in a breast cancer sample; somatic mutation. Ref.14

VAR_036044

Natural variant

500

1

S → G. Ref.1 Ref.3
Corresponds to variant rs2228331 [ dbSNP | Ensembl ].

VAR_033977

Experimental info

Mutagenesis

79

1

N → Q: Protein yield reduced by half. Protein yield reduced by 90%, abolishes N-glycosylation but no effect on secondary structure; when associated with Q-116. Ref.11

Mutagenesis

116

1

N → Q: No effect on protein yield. Protein yield reduced by 90%, abolishes N-glycosylation but no effect on secondary structure; when associated with Q-79. Ref.11

Secondary structure

1

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558

Helix Strand Turn

Details...

Helix

33 – 40

8

Turn

41 – 43

3

Beta strand

46 – 49

4

Beta strand

60 – 62

3

Beta strand

64 – 68

5

Helix

71 – 125

55

Turn

127 – 129

3

Helix

132 – 152

21

Helix

167 – 173

7

Helix

206 – 237

32

Helix

244 – 253

10

Helix

256 – 259

4

Helix

269 – 284

16

Helix

287 – 299

13

Helix

300 – 304

5

Helix

310 – 315

6

Helix

374 – 388

15

Helix

392 – 402

11

Beta strand

418 – 422

5

Beta strand

431 – 433

3

Helix

434 – 436

3

Beta strand

440 – 442

3

Helix

451 – 471

21

Sequences

	Sequence		Length	Mass (Da)
	P35052 [UniParc]. Last modified March 23, 2010. Version 2. Checksum: 16553B56080A83C8	FASTA	558	61,680
	10 20 30 40 50 60 MELRARGWWL LCAAAALVAC ARGDPASKSR SCGEVRQIYG AKGFSLSDVP QAEISGEHLR 70 80 90 100 110 120 ICPQGYTCCT SEMEENLANR SHAELETALR DSSRVLQAML ATQLRSFDDH FQHLLNDSER 130 140 150 160 170 180 TLQATFPGAF GELYTQNARA FRDLYSELRL YYRGANLHLE ETLAEFWARL LERLFKQLHP 190 200 210 220 230 240 QLLLPDDYLD CLGKQAEALR PFGEAPRELR LRATRAFVAA RSFVQGLGVA SDVVRKVAQV 250 260 270 280 290 300 PLGPECSRAV MKLVYCAHCL GVPGARPCPD YCRNVLKGCL ANQADLDAEW RNLLDSMVLI 310 320 330 340 350 360 TDKFWGTSGV ESVIGSVHTW LAEAINALQD NRDTLTAKVI QGCGNPKVNP QGPGPEEKRR 370 380 390 400 410 420 RGKLAPRERP PSGTLEKLVS EAKAQLRDVQ DFWISLPGTL CSEKMALSTA SDDRCWNGMA 430 440 450 460 470 480 RGRYLPEVMG DGLANQINNP EVEVDITKPD MTIRQQIMQL KIMTNRLRSA YNGNDVDFQD 490 500 510 520 530 540 ASDDGSGSGS GDGCLDDLCS RKVSRKSSSS RTPLTHALPG LSEQEGQKTS AASCPQPPTF 550 LLPLLLFLAL TVARPRWR

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Molecular cloning of a phosphatidylinositol-anchored membrane heparan sulfate proteoglycan from human lung fibroblasts." David G., Lories V., Decock B., Marynen P., Cassiman J.-J., van den Berghe H. J. Cell Biol. 111:3165-3176(1990) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 24-53; 100-118 AND 298-317, GPI-ANCHOR, GLYCOSYLATION AT ASN-116, VARIANT GLY-500. Tissue: Lung fibroblast.
[2]	"Generation and annotation of the DNA sequences of human chromosomes 2 and 4." Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H. , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K. Nature 434:724-731(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT GLY-500. Tissue: Salivary gland.
[4]	"Prion, amyloid beta-derived Cu(II) ions, or free Zn(II) ions support S-nitroso-dependent autocleavage of glypican-1 heparan sulfate." Mani K., Cheng F., Havsmark B., Jonsson M., Belting M., Fransson L.A. J. Biol. Chem. 278:38956-38965(2003) [PubMed] [Europe PMC] [Abstract] Cited for: COPPER-BINDING, NITROSYLATION, GLYCOSYLATION.
[5]	"Glypican-1 as an Abeta binding HSPG in the human brain: its localization in DIG domains and possible roles in the pathogenesis of Alzheimer's disease." Watanabe N., Araki W., Chui D.H., Makifuchi T., Ihara Y., Tabira T. FASEB J. 18:1013-1015(2004) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, POSSIBLE ASSOCIATION WITH ALZHEIMER DISEASE.
[6]	"Defective nitric oxide-dependent, deaminative cleavage of glypican-1 heparan sulfate in Niemann-Pick C1 fibroblasts." Mani K., Cheng F., Fransson L.A. Glycobiology 16:711-718(2006) [PubMed] [Europe PMC] [Abstract] Cited for: S-NITROSYLATION, ASSOCIATION WITH NIEMANN-PICK TYPE C1 DISEASE.
[7]	"Constitutive and vitamin C-induced, NO-catalyzed release of heparan sulfate from recycling glypican-1 in late endosomes." Mani K., Cheng F., Fransson L.A. Glycobiology 16:1251-1261(2006) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, NITROSYLATION, GLYCOSYLATION.
[8]	"Chemical and thermal unfolding of glypican-1: protective effect of heparan sulfate against heat-induced irreversible aggregation." Svensson G., Linse S., Mani K. Biochemistry 48:9994-10004(2009) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION, ABSENCE OF GLYCOSYLATION AT SER-55.
[9]	"S-Nitrosylation of secreted recombinant human glypican-1." Svensson G., Mani K. Glycoconj. J. 26:1247-1257(2009) [PubMed] [Europe PMC] [Abstract] Cited for: NITROSYLATION, SUBCELLULAR LOCATION, GLYCOSYLATION.
[10]	"Glypican-1 mediates both prion protein lipid raft association and disease isoform formation." Taylor D.R., Whitehouse I.J., Hooper N.M. PLoS Pathog. 5:E1000666-E1000666(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
[11]	"The structural role of N-linked glycans on human glypican-1." Svensson G., Hyrenius Wittsten A., Linse S., Mani K. Biochemistry 50:9377-9387(2011) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION AT ASN-79 AND ASN-116, MUTAGENESIS OF ASN-79 AND ASN-116.
[12]	"Suppression of amyloid beta A11 antibody immunoreactivity by vitamin C: possible role of heparan sulfate oligosaccharides derived from glypican-1 by ascorbate-induced, nitric oxide (NO)-catalyzed degradation." Cheng F., Cappai R., Ciccotosto G.D., Svensson G., Multhaup G., Fransson L.A., Mani K. J. Biol. Chem. 286:27559-27572(2011) [PubMed] [Europe PMC] [Abstract] Cited for: NITROSYLATION, GLYCOSYLATION, FUNCTION.
[13]	"Crystal structure of N-glycosylated human glypican-1 core protein: Structure of two loops evolutionarily conserved in vertebrate glypican-1." Svensson G., Awad W., Hakansson M., Mani K., Logan D.T. J. Biol. Chem. 287:14040-14051(2012) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS), DISULFIDE BONDS, LACK OF GLYCOSYLATION AT SER-55, GLYCOSYLATION AT ASN-79 AND ASN-116.
[14]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT [LARGE SCALE ANALYSIS] ASP-337.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X54232 mRNA. Translation: CAA38139.1.
AC110619 Genomic DNA. Translation: AAY24160.1.
BC051279 mRNA. Translation: AAH51279.1.

IPI

IPI00015688.

PIR

A36347.

RefSeq

NP_002072.2. NM_002081.2.

UniGene

Hs.328232.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
4ACR	X-ray	2.55	A/B/C/D	24-479	[»]
4AD7	X-ray	2.94	A/B/C/D	24-529	[»]

ProteinModelPortal

P35052.

SMR

P35052. Positions 29-475.

ModBase

Search...

Protein-protein interaction databases

STRING

9606.ENSP00000264039.

PTM databases

PhosphoSite

P35052.

Polymorphism databases

DMDM

292495012.

Proteomic databases

PaxDb

P35052.

PRIDE

P35052.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000264039; ENSP00000264039; ENSG00000063660.

GeneID

2817.

KEGG

hsa:2817.

UCSC

uc002vyw.4. human.

Organism-specific databases

CTD

2817.

GeneCards

GC02P241378.

H-InvDB

HIX0002996.

HGNC

HGNC:4449. GPC1.

HPA

HPA030571.

MIM

600395. gene.

neXtProt

NX_P35052.

PharmGKB

PA28830.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG235988.

HOGENOM

HOG000253003.

HOVERGEN

HBG003464.

InParanoid

P35052.

KO

K08107.

OrthoDB

EOG4TXBRP.

PhylomeDB

P35052.

Enzyme and pathway databases

Pathway_Interaction_DB

glypican_1pathway. Glypican 1 network.
glypicanpathway. Glypican pathway.

Reactome

REACT_111045. Developmental Biology.
REACT_111217. Metabolism.
REACT_116125. Disease.

Gene expression databases

ArrayExpress

P35052.

Bgee

P35052.

CleanEx

HS_GPC1.

Genevestigator

P35052.

Family and domain databases

InterPro

IPR001863. Glypican.
IPR015502. Glypican-1.
IPR019803. Glypican_CS.
[Graphical view]

PANTHER

PTHR10822. PTHR10822. 1 hit.
PTHR10822:SF8. PTHR10822:SF8. 1 hit.

Pfam

PF01153. Glypican. 1 hit.
[Graphical view]

PROSITE

PS01207. GLYPICAN. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

GenomeRNAi

2817.

NextBio

11103.

SOURCE

Search...

Entry information

Entry name

GPC1_HUMAN

Accession

Primary (citable) accession number: P35052
Secondary accession number(s): Q53QM4

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1994
Last sequence update:	March 23, 2010
Last modified:	April 3, 2013
This is version 108 of the entry and version 2 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.