P28799 (GRN_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Granulins

Alternative name(s):
Proepithelin
Short name=PEPI

Cleaved into the following 9 chains:

1. Acrogranin
2. Paragranulin
3. Granulin-1
   Alternative name(s):
   Granulin G
4. Granulin-2
   Alternative name(s):
   Granulin F
5. Granulin-3
   Alternative name(s):
   Granulin B
6. Granulin-4
   Alternative name(s):
   Granulin A
7. Granulin-5
   Alternative name(s):
   Granulin C
8. Granulin-6
   Alternative name(s):
   Granulin D
9. Granulin-7
   Alternative name(s):
   Granulin E

Gene names

Name:

GRN

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	593 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	Granulins have possible cytokine-like activity. They may play a role in inflammation, wound repair, and tissue remodeling. Granulin-4 promotes proliferation of the epithelial cell line A431 in culture while granulin-3 acts as an antagonist to granulin-4, inhibiting the growth.
Subcellular location	Secreted.
Tissue specificity	In myelogenous leukemic cell lines of promonocytic, promyelocytic, and proerythroid lineage, in fibroblasts, and very strongly in epithelial cell lines. Present in inflammatory cells and bone marrow. Highest levels in kidney.
Post-translational modification	Granulins are disulfide bridged.
Involvement in disease	Ubiquitin-positive frontotemporal dementia (UP-FTD) [MIM:607485]: Frontotemporal dementia (FTD) is the second most common cause of dementia in people under the age of 65 years. It is an autosomal dominant neurodegenerative disease. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.11 Ref.15 Ref.16 Neuronal ceroid lipofuscinosis 11 (CLN11) [MIM:614706]: A form of neuronal ceroid lipofuscinosis characterized by rapidly progressive visual loss due to retinal dystrophy, seizures, cerebellar ataxia, and cerebellar atrophy. Cognitive decline may also occur. Neuronal ceroid lipofuscinoses are progressive neurodegenerative, lysosomal storage diseases characterized by intracellular accumulation of autofluorescent liposomal material. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.13
Sequence similarities	Belongs to the granulin family.

Ontologies

Keywords
Cellular component	Secreted
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Neurodegeneration Neuronal ceroid lipofuscinosis
Domain	Repeat Signal
Molecular function	Cytokine
PTM	Disulfide bond Glycoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	blastocyst hatching Inferred from electronic annotation. Source: Compara cell death Inferred from electronic annotation. Source: UniProtKB-KW embryo implantation Inferred from electronic annotation. Source: Compara positive regulation of epithelial cell proliferation Inferred from electronic annotation. Source: Compara signal transduction Non-traceable author statement Ref.3. Source: ProtInc
Cellular_component	extracellular space Inferred from electronic annotation. Source: UniProtKB-KW intracellular membrane-bounded organelle Inferred from direct assay. Source: HPA mitochondrion Inferred from electronic annotation. Source: Compara
Molecular_function	growth factor activity Traceable author statement Ref.3. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CACNA1A	O00555	2	EBI-747754,EBI-766279
Hoxa1	P09022	2	EBI-747754,EBI-3957603	From a different organism.

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P28799-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: P28799-2)

The sequence of this isoform differs from the canonical sequence as follows:
     377-531: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 17

17

Potential

Chain

18 – 593

576

Acrogranin

PRO_0000012693

Peptide

18 – ?47

30

Paragranulin

PRO_0000012694

Peptide

?58 – ?113

56

Granulin-1

PRO_0000012695

Peptide

?123 – ?179

57

Granulin-2

PRO_0000012696

Peptide

206 – 261

56

Granulin-3

PRO_0000012697

Peptide

281 – 336

56

Granulin-4

PRO_0000012698

Peptide

364 – ?417

54

Granulin-5

PRO_0000012699

Peptide

442 – ?496

55

Granulin-6

PRO_0000012700

Peptide

?518 – ?573

56

Granulin-7

PRO_0000012701

Amino acid modifications

Glycosylation

118

1

N-linked (GlcNAc...) Potential

Glycosylation

236

1

N-linked (GlcNAc...) Potential

Glycosylation

265

1

N-linked (GlcNAc...) Ref.12

Glycosylation

368

1

N-linked (GlcNAc...)

Glycosylation

530

1

N-linked (GlcNAc...) Potential

Disulfide bond

284 ↔ 296

Disulfide bond

290 ↔ 306

Natural variations

Alternative sequence

377 – 531

155

Missing in isoform 2.

VSP_001837

Natural variant

9

1

A → D in UP-FTD; no significant difference in the total mRNA between cases and controls; although the mutant protein is expressed it is not secreted and appears to be trapped within an intracellular compartment. Ref.15 Ref.16

VAR_044451

Natural variant

19

1

R → W. Ref.17

VAR_064625

Natural variant

55

1

R → W. Ref.17

VAR_064626

Natural variant

69

1

A → T. Ref.17

VAR_064627

Natural variant

119

1

Missing. Ref.17

VAR_064628

Natural variant

120

1

S → Y. Ref.17

VAR_064629

Natural variant

182

1

T → M. Ref.17

VAR_064630

Natural variant

221

1

C → S. Ref.17

VAR_064631

Natural variant

275

1

P → L. Ref.17

VAR_064632

Natural variant

376

1

D → N. Ref.17

VAR_064633

Natural variant

398

1

S → L. Ref.17

VAR_064634

Natural variant

433

1

R → Q. Ref.17

VAR_064635

Natural variant

515

1

G → A. Ref.17
Corresponds to variant rs25647 [ dbSNP | Ensembl ].

VAR_014830

Natural variant

564

1

R → H. Ref.17

VAR_064636

Experimental info

Sequence conflict

219

1

S → H AA sequence Ref.9

Sequence conflict

290

1

C → S AA sequence Ref.10

Sequence conflict

386

1

W → H AA sequence Ref.9

Sequence conflict

454

1

Q → G in AAA58617. Ref.3

Secondary structure

1

.

.

.

.

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.

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.

.

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.

.

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593

Helix Strand Turn

Details...

Beta strand

137 – 141

5

Beta strand

143 – 145

3

Beta strand

147 – 151

5

Beta strand

288 – 290

3

Beta strand

294 – 298

5

Beta strand

304 – 308

5

Beta strand

315 – 319

5

Turn

330 – 333

4

Turn

367 – 369

3

Beta strand

377 – 380

4

Beta strand

382 – 384

3

Beta strand

386 – 389

4

Turn

399 – 402

4

Beta strand

409 – 411

3

Turn

412 – 414

3

Beta strand

415 – 417

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified October 11, 2005. Version 2. Checksum: 4E5947F1B4EDE619	FASTA	593	63,544
	10 20 30 40 50 60 MWTLVSWVAL TAGLVAGTRC PDGQFCPVAC CLDPGGASYS CCRPLLDKWP TTLSRHLGGP 70 80 90 100 110 120 CQVDAHCSAG HSCIFTVSGT SSCCPFPEAV ACGDGHHCCP RGFHCSADGR SCFQRSGNNS 130 140 150 160 170 180 VGAIQCPDSQ FECPDFSTCC VMVDGSWGCC PMPQASCCED RVHCCPHGAF CDLVHTRCIT 190 200 210 220 230 240 PTGTHPLAKK LPAQRTNRAV ALSSSVMCPD ARSRCPDGST CCELPSGKYG CCPMPNATCC 250 260 270 280 290 300 SDHLHCCPQD TVCDLIQSKC LSKENATTDL LTKLPAHTVG DVKCDMEVSC PDGYTCCRLQ 310 320 330 340 350 360 SGAWGCCPFT QAVCCEDHIH CCPAGFTCDT QKGTCEQGPH QVPWMEKAPA HLSLPDPQAL 370 380 390 400 410 420 KRDVPCDNVS SCPSSDTCCQ LTSGEWGCCP IPEAVCCSDH QHCCPQGYTC VAEGQCQRGS 430 440 450 460 470 480 EIVAGLEKMP ARRASLSHPR DIGCDQHTSC PVGQTCCPSL GGSWACCQLP HAVCCEDRQH 490 500 510 520 530 540 CCPAGYTCNV KARSCEKEVV SAQPATFLAR SPHVGVKDVE CGEGHFCHDN QTCCRDNRQG 550 560 570 580 590 WACCPYRQGV CCADRRHCCP AGFRCAARGT KCLRREAPRW DAPLRDPALR QLL
	Isoform 2 [UniParc]. Checksum: 558B72CBAF3B991F	FASTA	438	46,991
	10 20 30 40 50 60 MWTLVSWVAL TAGLVAGTRC PDGQFCPVAC CLDPGGASYS CCRPLLDKWP TTLSRHLGGP 70 80 90 100 110 120 CQVDAHCSAG HSCIFTVSGT SSCCPFPEAV ACGDGHHCCP RGFHCSADGR SCFQRSGNNS 130 140 150 160 170 180 VGAIQCPDSQ FECPDFSTCC VMVDGSWGCC PMPQASCCED RVHCCPHGAF CDLVHTRCIT 190 200 210 220 230 240 PTGTHPLAKK LPAQRTNRAV ALSSSVMCPD ARSRCPDGST CCELPSGKYG CCPMPNATCC 250 260 270 280 290 300 SDHLHCCPQD TVCDLIQSKC LSKENATTDL LTKLPAHTVG DVKCDMEVSC PDGYTCCRLQ 310 320 330 340 350 360 SGAWGCCPFT QAVCCEDHIH CCPAGFTCDT QKGTCEQGPH QVPWMEKAPA HLSLPDPQAL 370 380 390 400 410 420 KRDVPCDNVS SCPSSDTCCR DNRQGWACCP YRQGVCCADR RHCCPAGFRC AARGTKCLRR 430 EAPRWDAPLR DPALRQLL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Structure and chromosomal location of the human granulin gene." Bhandari V., Bateman A. Biochem. Biophys. Res. Commun. 188:57-63(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], SEQUENCE REVISION.
[2]	"The epithelin precursor encodes two proteins with opposing activities on epithelial cell growth." Plowman G.D., Green J.M., Neubauer M.G., Buckley S.D., McDonald V.L., Todaro G.J., Shoyab M. J. Biol. Chem. 267:13073-13078(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Kidney.
[3]	"Isolation and sequence of the granulin precursor cDNA from human bone marrow reveals tandem cysteine-rich granulin domains." Bhandari V., Palfree R.G.E., Bateman A. Proc. Natl. Acad. Sci. U.S.A. 89:1715-1719(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE. Tissue: Bone marrow.
[4]	"PCDGF sequence from lambda phage human Jurkat T cell cDNA library (Clontech)." Lu R., Tian C., Serrero G. Submitted (JUN-2002) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[5]	Yu W., Gibbs R.A. Submitted (MAR-1998) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain.
[6]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
[7]	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].
[8]	"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] (ISOFORMS 1 AND 2). Tissue: Cervix and Lung.
[9]	"Granulins, a novel class of peptide from leukocytes." Bateman A., Belcourt D.R., Bennett H.P., Lazure C., Solomon S. Biochem. Biophys. Res. Commun. 173:1161-1168(1990) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 206-233; 281-336; 364-396 AND 442-447. Tissue: Leukocyte.
[10]	"Characterisation of UGP and its relationship with beta-core fragment." Kardana A., Bagshawe K.D., Coles B., Read D., Taylor M. Br. J. Cancer 67:686-692(1993) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 281-295.
[11]	"Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17." Baker M., Mackenzie I.R., Pickering-Brown S.M., Gass J., Rademakers R., Lindholm C., Snowden J., Adamson J., Sadovnick A.D., Rollinson S., Cannon A., Dwosh E., Neary D., Melquist S., Richardson A., Dickson D., Berger Z., Eriksen J. , Robinson T., Zehr C., Dickey C.A., Crook R., McGowan E., Mann D., Boeve B., Feldman H., Hutton M. Nature 442:916-919(2006) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN UP-FTD.
[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] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-265, MASS SPECTROMETRY. Tissue: Liver.
[13]	"Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage." Smith K.R., Damiano J., Franceschetti S., Carpenter S., Canafoglia L., Morbin M., Rossi G., Pareyson D., Mole S.E., Staropoli J.F., Sims K.B., Lewis J., Lin W.L., Dickson D.W., Dahl H.H., Bahlo M., Berkovic S.F. Am. J. Hum. Genet. 90:1102-1107(2012) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN CLN11.
[14]	"Design and solution structure of a well-folded stack of two beta-hairpins based on the amino-terminal fragment of human granulin A." Tolkatchev D., Ng A., Vranken W., Ni F. Biochemistry 39:2878-2886(2000) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 284-311.
[15]	"HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin." Mukherjee O., Pastor P., Cairns N.J., Chakraverty S., Kauwe J.S.K., Shears S., Behrens M.I., Budde J., Hinrichs A.L., Norton J., Levitch D., Taylor-Reinwald L., Gitcho M., Tu P.-H., Tenenholz Grinberg L., Liscic R.M., Armendariz J., Morris J.C., Goate A.M. Ann. Neurol. 60:314-322(2006) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT UP-FTD ASP-9.
[16]	"Molecular characterization of novel progranulin (GRN) mutations in frontotemporal dementia." Mukherjee O., Wang J., Gitcho M., Chakraverty S., Taylor-Reinwald L., Shears S., Kauwe J.S.K., Norton J., Levitch D., Bigio E.H., Hatanpaa K.J., White C.L., Morris J.C., Cairns N.J., Goate A. Hum. Mutat. 29:512-521(2008) [PubMed] [Europe PMC] [Abstract] Cited for: CHARACTERIZATION OF VARIANT UP-FTD ASP-9.
[17]	"A thorough assessment of benign genetic variability in GRN and MAPT." Guerreiro R.J., Washecka N., Hardy J., Singleton A. Hum. Mutat. 31:E1126-E1140(2010) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS TRP-19; TRP-55; THR-69; ASN-119 DEL; TYR-120; MET-182; SER-221; LEU-275; ASN-376; LEU-398; GLN-433; ALA-515 AND HIS-564.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X62320 mRNA. Translation: CAA44196.1.
AF055008 mRNA. Translation: AAC09359.1.
M75161 mRNA. Translation: AAA58617.1. Sequence problems.
AY124489 mRNA. Translation: AAM94026.1.
BT006844 mRNA. Translation: AAP35490.1.
CH471178 Genomic DNA. Translation: EAW51599.1.
CH471178 Genomic DNA. Translation: EAW51600.1.
BC000324 mRNA. Translation: AAH00324.1.
BC010577 mRNA. Translation: AAH10577.1.

IPI

IPI00182138.
IPI00296713.

PIR

GYHU. JC1284.

RefSeq

NP_002078.1. NM_002087.2.

UniGene

Hs.514220.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1G26	NMR	-	A	284-311	[»]
2JYE	NMR	-	A	281-337	[»]
2JYT	NMR	-	A	364-417	[»]
2JYU	NMR	-	A	364-417	[»]
2JYV	NMR	-	A	123-179	[»]

ProteinModelPortal

P28799.

ModBase

Search...

Protein-protein interaction databases

IntAct

P28799. 36 interactions.

MINT

MINT-271687.

STRING

9606.ENSP00000053867.

PTM databases

PhosphoSite

P28799.

Polymorphism databases

DMDM

77416865.

Proteomic databases

PaxDb

P28799.

PRIDE

P28799.

Protocols and materials databases

DNASU

2896.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000053867; ENSP00000053867; ENSG00000030582.

GeneID

2896.

KEGG

hsa:2896.

UCSC

uc002igp.1. human.

Organism-specific databases

CTD

2896.

GeneCards

GC17P042422.

HGNC

HGNC:4601. GRN.

HPA

CAB019394.
HPA008763.
HPA028747.

MIM

138945. gene.
607485. phenotype.
614706. phenotype.

neXtProt

NX_P28799.

Orphanet

314629. CLN11 disease.
100070. Progressive non-fluent aphasia.

PharmGKB

PA28998.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG270518.

HOVERGEN

HBG000845.

InParanoid

P28799.

OMA

PSSNTCC.

OrthoDB

EOG4T7837.

PhylomeDB

P28799.

Gene expression databases

Bgee

P28799.

CleanEx

HS_GRN.

Genevestigator

P28799.

GermOnline

ENSG00000030582. Homo sapiens.

Family and domain databases

InterPro

IPR006150. Cys_repeat_1.
IPR000118. Granulin.
[Graphical view]

Pfam

PF00396. Granulin. 7 hits.
[Graphical view]

SMART

SM00277. GRAN. 7 hits.
SM00289. WR1. 5 hits.
[Graphical view]

PROSITE

PS00799. GRANULINS. 7 hits.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

GRN. human.

EvolutionaryTrace

P28799.

GenomeRNAi

2896.

NextBio

11459.

PMAP-CutDB

P28799.

SOURCE

Search...

Entry information

Entry name

GRN_HUMAN

Accession

Primary (citable) accession number: P28799
Secondary accession number(s): D3DX55 , P23781, P23782, P23783, P23784, Q53Y88, Q540U8, Q9BWE7, Q9UCH0

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 1, 1992
Last sequence update:	October 11, 2005
Last modified:	May 29, 2013
This is version 145 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.