P01033 (TIMP1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Metalloproteinase inhibitor 1

Alternative name(s):
Erythroid-potentiating activity
Short name=EPA
Fibroblast collagenase inhibitor
Short name=Collagenase inhibitor
Tissue inhibitor of metalloproteinases 1
Short name=TIMP-1

Gene names

Name:	TIMP1
Synonyms:	CLGI, TIMP

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	207 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	Complexes with metalloproteinases (such as collagenases) and irreversibly inactivates them by binding to their catalytic zinc cofactor. Also mediates erythropoiesis in vitro; but, unlike IL-3, it is species-specific, stimulating the growth and differentiation of only human and murine erythroid progenitors. Known to act on MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-12, MMP-13 and MMP-16. Does not act on MMP-14.
Subcellular location	Secreted.
Post-translational modification	The activity of TIMP1 is dependent on the presence of disulfide bonds.
Sequence similarities	Belongs to the protease inhibitor I35 (TIMP) family. [View classification] Contains 1 NTR domain.

Ontologies

Keywords
Biological process	Erythrocyte maturation
Cellular component	Secreted
Domain	Signal
Ligand	Metal-binding Zinc
Molecular function	Metalloenzyme inhibitor Metalloprotease inhibitor Protease inhibitor
PTM	Disulfide bond Glycoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	aging Inferred from electronic annotation. Source: Compara erythrocyte maturation Inferred from electronic annotation. Source: UniProtKB-KW extracellular matrix disassembly Traceable author statement. Source: Reactome negative regulation of apoptotic process Inferred from electronic annotation. Source: Compara negative regulation of membrane protein ectodomain proteolysis Inferred from direct assay PubMed 12714508. Source: UniProtKB negative regulation of trophoblast cell migration Inferred from mutant phenotype PubMed 21356369. Source: BHF-UCL platelet activation Traceable author statement. Source: Reactome platelet degranulation Traceable author statement. Source: Reactome positive regulation of cell proliferation Traceable author statement Ref.2. Source: ProtInc response to cytokine stimulus Inferred from electronic annotation. Source: Compara response to peptide hormone stimulus Inferred from electronic annotation. Source: Compara
Cellular_component	basement membrane Inferred from electronic annotation. Source: Compara extracellular region Non-traceable author statement Ref.10. Source: UniProtKB platelet alpha granule lumen Traceable author statement. Source: Reactome
Molecular_function	metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW metalloendopeptidase inhibitor activity Inferred from direct assay PubMed 12714508. 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.9 Ref.10 Ref.11

Chain

24 – 207

184

Metalloproteinase inhibitor 1

PRO_0000034323

Regions

Domain

24 – 147

124

NTR

Region

24 – 28

5

Involved in metalloproteinase-binding

Region

90 – 91

2

Involved in metalloproteinase-binding

Sites

Metal binding

24

1

Zinc; via amino nitrogen and carbonyl oxygen; shared with metalloproteinase partner

Amino acid modifications

Glycosylation

53

1

N-linked (GlcNAc...) Ref.15 Ref.16 Ref.17

CAR_000002

Glycosylation

101

1

N-linked (GlcNAc...) Ref.16

CAR_000003

Disulfide bond

24 ↔ 93

Ref.13

Disulfide bond

26 ↔ 122

Ref.13

Disulfide bond

36 ↔ 147

Ref.13

Disulfide bond

150 ↔ 197

Ref.13

Disulfide bond

155 ↔ 160

Ref.13

Disulfide bond

168 ↔ 189

Ref.13

Experimental info

Mutagenesis

25

1

T → E, G, K, Q or R: Reduced interaction with metalloproteinase. Ref.22

Mutagenesis

25

1

T → V: Normal interaction with metalloproteinase. Ref.22

Sequence conflict

23

1

A → P in CAA26443. Ref.2

Sequence conflict

44

1

A → P in BAA01913. Ref.12

Secondary structure

1

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207

Helix Strand Turn

Details...

Helix

31 – 37

7

Beta strand

39 – 46

8

Beta strand

57 – 70

14

Helix

72 – 74

3

Turn

77 – 79

3

Beta strand

83 – 89

7

Helix

90 – 92

3

Beta strand

105 – 113

9

Beta strand

116 – 118

3

Beta strand

125 – 127

3

Helix

128 – 130

3

Helix

133 – 140

8

Helix

143 – 145

3

Turn

146 – 149

4

Beta strand

151 – 154

4

Beta strand

157 – 159

3

Beta strand

167 – 170

4

Helix

172 – 176

5

Beta strand

177 – 181

5

Helix

182 – 186

5

Beta strand

188 – 193

6

Beta strand

196 – 200

5

Sequences

	Sequence		Length	Mass (Da)
	P01033 [UniParc]. Last modified July 21, 1986. Version 1. Checksum: 5AE4F90FFAB2ECDC	FASTA	207	23,171
	10 20 30 40 50 60 MAPFEPLASG ILLLLWLIAP SRACTCVPPH PQTAFCNSDL VIRAKFVGTP EVNQTTLYQR 70 80 90 100 110 120 YEIKMTKMYK GFQALGDAAD IRFVYTPAME SVCGYFHRSH NRSEEFLIAG KLQDGLLHIT 130 140 150 160 170 180 TCSFVAPWNS LSLAQRRGFT KTYTVGCEEC TVFPCLSIPC KLQSGTHCLW TDQLLQGSEK 190 200 GFQSRHLACL PREPGLCTWQ SLRSQIA

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Sequence of human tissue inhibitor of metalloproteinases and its identity to erythroid-potentiating activity." Docherty A.J.P., Lyons A., Smith B.J., Wright E.M., Stephens P.E., Harris T.J.R., Murphy G., Reynolds J.J. Nature 318:66-69(1985) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Molecular characterization and expression of the gene encoding human erythroid-potentiating activity." Gasson J.C., Golde D.W., Kaufman S.E., Westbrook C.A., Hewick R.M., Kaufman R.J., Wong G.G., Temple P.A., Leary A.C., Brown E.L., Orr E.C., Clark S.C. Nature 315:768-771(1985) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Primary structure and cDNA cloning of human fibroblast collagenase inhibitor." Carmichael D.F., Sommer A., Thompson R.C., Anderson D.C., Smith C.G., Welgus H.G., Stricklin G.P. Proc. Natl. Acad. Sci. U.S.A. 83:2407-2411(1986) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[4]	"Molecular cloning and synthesis of biologically active human tissue inhibitor of metalloproteinases in yeast." Kaczorek M., Honore N., Ribes V., Dehoux P., Cornet P., Cartwright T., Streeck R.E. Biotechnology (N.Y.) 5:595-598(1987) Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[5]	"Characterization of three abundant mRNAs from human ovarian granulosa cells." Rapp G., Freudenstein J., Klaudiny J., Mucha J., Wempe F., Zimmer M., Scheit K.H. DNA Cell Biol. 9:479-485(1990) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Ovary.
[6]	"Characterization of a human corneal metalloproteinase inhibitor (TIMP-1)." Opbroek A., Kenney M.C., Brown D. Curr. Eye Res. 12:877-883(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[7]	"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]. Tissue: Cervix.
[8]	"Genomic organization of the human TIMP-1 gene. Investigation of a causative role in the pathogenesis of X-linked retinitis pigmentosa 2." Hardcastle A.J., Thiselton D.L., Nayudu M., Hampson R.M., Bhattacharya S.S. Invest. Ophthalmol. Vis. Sci. 38:1893-1896(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-40.
[9]	"Isolation and characterization of tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) from human rheumatoid synovial fluid." Osthues A., Knaueper V., Oberhoff R., Reinke H., Tschesche H. FEBS Lett. 296:16-20(1992) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 24-38. Tissue: Synovial fluid.
[10]	"The cytokine-protease connection: identification of a 96-kD THP-1 gelatinase and regulation by interleukin-1 and cytokine inducers." van Ranst M., Norga K., Masure S., Proost P., Vandekerckhove F., Auwerx J., van Damme J., Opdenakker G. Cytokine 3:231-239(1991) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 24-52.
[11]	"Signal peptide prediction based on analysis of experimentally verified cleavage sites." Zhang Z., Henzel W.J. Protein Sci. 13:2819-2824(2004) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 24-38.
[12]	Matsuda T., Kohno K., Kuwano M. Submitted (JUL-1992) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 42-207.
[13]	"Disulphide bond assignment in human tissue inhibitor of metalloproteinases (TIMP)." Williamson R.A., Martson F.A.O., Angal S., Koklitis P., Panico M., Morris H.R., Carne A.F., Smith B.J., Harris T.J.R., Freedman R.B. Biochem. J. 268:267-274(1990) [PubMed] [Europe PMC] [Abstract] Cited for: DISULFIDE BONDS, PARTIAL PROTEIN SEQUENCE.
[14]	"Site-directed mutations that alter the inhibitory activity of the tissue inhibitor of metalloproteinases-1: importance of the N-terminal region between cysteine 3 and cysteine 13." O'Shea M., Willenbrock F., Williamson R.A., Cockett M.I., Freedman R.B., Reynolds J.J., Docherty A.J.P., Murphy G. Biochemistry 31:10146-10152(1992) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS.
[15]	"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-53, MASS SPECTROMETRY. Tissue: Plasma.
[16]	"Identification of N-linked glycoproteins in human saliva by glycoprotein capture and mass spectrometry." Ramachandran P., Boontheung P., Xie Y., Sondej M., Wong D.T., Loo J.A. J. Proteome Res. 5:1493-1503(2006) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-53 AND ASN-101, MASS SPECTROMETRY. Tissue: Saliva.
[17]	"Elucidation of N-glycosylation sites on human platelet proteins: a glycoproteomic approach." Lewandrowski U., Moebius J., Walter U., Sickmann A. Mol. Cell. Proteomics 5:226-233(2006) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-53, MASS SPECTROMETRY. Tissue: Platelet.
[18]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[19]	"Mechanism of inhibition of the human matrix metalloproteinase stromelysin-1 by TIMP-1." Gomis-Rueth F.-X., Maskos K., Betz M., Bergner A., Huber R., Suzuki K., Yoshida N., Nagase H., Brew K., Bourenkov G.P., Bartunik H., Bode W. Nature 389:77-81(1997) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) OF 24-207 IN COMPLEX WITH MMP-3.
[20]	"NMR structure of tissue inhibitor of metalloproteinases-1 implicates localized induced fit in recognition of matrix metalloproteinases." Wu B., Arumugam S., Gao G., Lee G.I., Semenchenko V., Huang W., Brew K., Van Doren S.R. J. Mol. Biol. 295:257-268(2000) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 24-149.
[21]	"Global orientation of bound MMP-3 and N-TIMP-1 in solution via residual dipolar couplings." Arumugam S., Van Doren S.R. Biochemistry 42:7950-7958(2003) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 24-149 IN COMPLEX WITH MMP-3.
[22]	"Crystal structure of the catalytic domain of matrix metalloproteinase-1 in complex with the inhibitory domain of tissue inhibitor of metalloproteinase-1." Iyer S., Wei S., Brew K., Acharya K.R. J. Biol. Chem. 282:364-371(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.54 ANGSTROMS) OF 24-149 IN COMPLEX WITH MMP-1, COFACTOR, MUTAGENESIS OF THR-25.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X03124 mRNA. Translation: CAA26902.1.
X02598 mRNA. Translation: CAA26443.1.
M12670 mRNA. Translation: AAA52436.1.
M59906 mRNA. Translation: AAA63234.1.
S68252 mRNA. Translation: AAD14009.1.
BC000866 mRNA. Translation: AAH00866.1.
L47361 Genomic DNA. Translation: AAA75558.1.
D11139 Genomic DNA. Translation: BAA01913.1.

IPI

IPI00032292.

PIR

ZYHUEP. A93372.

RefSeq

NP_003245.1. NM_003254.2.

UniGene

Hs.522632.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1D2B	NMR	-	A	24-149	[»]
1LQN	model	-	A	1-207	[»]
1OO9	NMR	-	B	24-149	[»]
1UEA	X-ray	2.80	B/D	24-207	[»]
2J0T	X-ray	2.54	D/E/F	24-149	[»]
3MA2	X-ray	2.05	B/C	24-148	[»]
3V96	X-ray	1.90	A	24-207	[»]

ProteinModelPortal

P01033.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-1107N.

IntAct

P01033. 4 interactions.

MINT

MINT-2981826.

STRING

9606.ENSP00000218388.

Protein family/group databases

MEROPS

I35.001.

PTM databases

GlycoSuiteDB

P01033.

PhosphoSite

P01033.

Polymorphism databases

DMDM

135850.

Proteomic databases

PaxDb

P01033.

PRIDE

P01033.

Protocols and materials databases

DNASU

7076.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000218388; ENSP00000218388; ENSG00000102265.

GeneID

7076.

KEGG

hsa:7076.

UCSC

uc004dif.3. human.

Organism-specific databases

CTD

7076.

GeneCards

GC0XP047441.

HGNC

HGNC:11820. TIMP1.

HPA

CAB022360.

MIM

305370. gene.

neXtProt

NX_P01033.

PharmGKB

PA36526.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG259409.

HOGENOM

HOG000285981.

HOVERGEN

HBG068749.

InParanoid

P01033.

KO

K16451.

OMA

SSIPCKL.

OrthoDB

EOG44J2K2.

PhylomeDB

P01033.

Enzyme and pathway databases

Pathway_Interaction_DB

il6_7pathway. IL6-mediated signaling events.

Reactome

REACT_118779. Extracellular matrix organization.
REACT_604. Hemostasis.

Gene expression databases

ArrayExpress

P01033.

Bgee

P01033.

CleanEx

HS_TIMP1.

Genevestigator

P01033.

GermOnline

ENSG00000102265. Homo sapiens.

Family and domain databases

Gene3D

3.90.370.10. 1 hit.

InterPro

IPR001134. Netrin_domain.
IPR001820. Prot_inh_TIMP.
IPR008993. TIMP-like_OB-fold.
IPR015611. TIMP1.
IPR027465. TIMP_C_dom.
[Graphical view]

PANTHER

PTHR11844. PTHR11844. 1 hit.
PTHR11844:SF5. PTHR11844:SF5. 1 hit.

Pfam

PF00965. TIMP. 1 hit.
[Graphical view]

SMART

SM00206. NTR. 1 hit.
[Graphical view]

SUPFAM

SSF50242. TIMP_like. 1 hit.

PROSITE

PS50189. NTR. 1 hit.
PS00288. TIMP. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

P01033.

GenomeRNAi

7076.

NextBio

27675.

PMAP-CutDB

P01033.

SOURCE

Search...

Entry information

Entry name

TIMP1_HUMAN

Accession

Primary (citable) accession number: P01033
Secondary accession number(s): Q14252, Q9UCU1

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 21, 1986
Last sequence update:	July 21, 1986
Last modified:	May 29, 2013
This is version 157 of the entry and version 1 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.