P22894 (MMP8_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Neutrophil collagenase
EC=3.4.24.34

Alternative name(s):
Matrix metalloproteinase-8
Short name=MMP-8
PMNL collagenase
Short name=PMNL-CL

Gene names

Name:	MMP8
Synonyms:	CLG1

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	467 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	Can degrade fibrillar type I, II, and III collagens.
Catalytic activity	Cleavage of interstitial collagens in the triple helical domain. Unlike EC 3.4.24.7, this enzyme cleaves type III collagen more slowly than type I.
Cofactor	Binds 3 calcium ions per subunit. Binds 2 zinc ions per subunit.
Enzyme regulation	Cannot be activated without removal of the activation peptide.
Subcellular location	Cytoplasmic granule. Secreted › extracellular space › extracellular matrix Probable. Note: Stored in intracellular granules.
Tissue specificity	Neutrophils.
Domain	The conserved cysteine present in the cysteine-switch motif binds the catalytic zinc ion, thus inhibiting the enzyme. The dissociation of the cysteine from the zinc ion upon the activation-peptide release activates the enzyme.
Sequence similarities	Belongs to the peptidase M10A family. Contains 4 hemopexin-like domains.

Ontologies

Keywords
Biological process	Collagen degradation
Cellular component	Extracellular matrix Secreted
Coding sequence diversity	Polymorphism
Domain	Repeat Signal
Ligand	Calcium Metal-binding Zinc
Molecular function	Hydrolase Metalloprotease Protease
PTM	Disulfide bond Glycoprotein Zymogen
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	collagen catabolic process Inferred from electronic annotation. Source: UniProtKB-KW extracellular matrix disassembly Traceable author statement. Source: Reactome proteolysis Inferred from direct assay Ref.1. Source: UniProtKB
Cellular_component	extracellular space Inferred from direct assay Ref.1. Source: UniProtKB proteinaceous extracellular matrix Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	calcium ion binding Inferred from electronic annotation. Source: InterPro metalloendopeptidase activity Inferred from electronic annotation. Source: InterPro serine-type endopeptidase activity Inferred from direct assay PubMed 16192646Ref.1. Source: UniProtKB zinc ion binding Traceable author statement Ref.1. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 20

20

Ref.4 Ref.5

Propeptide

21 – 100

80

Activation peptide

PRO_0000028744

Chain

101 – 467

367

Neutrophil collagenase

PRO_0000028745

Regions

Domain

285 – 327

43

Hemopexin-like 1

Domain

329 – 372

44

Hemopexin-like 2

Domain

377 – 422

46

Hemopexin-like 3

Domain

424 – 464

41

Hemopexin-like 4

Motif

89 – 96

8

Cysteine switch By similarity

Sites

Active site

218

1

Metal binding

91

1

Zinc 2; in inhibited form

Metal binding

157

1

Calcium 1

Metal binding

167

1

Zinc 1 Ref.10

Metal binding

169

1

Zinc 1 Ref.10

Metal binding

174

1

Calcium 2 Ref.10

Metal binding

175

1

Calcium 2; via carbonyl oxygen Ref.10

Metal binding

177

1

Calcium 2; via carbonyl oxygen Ref.10

Metal binding

179

1

Calcium 2; via carbonyl oxygen Ref.10

Metal binding

182

1

Zinc 1 Ref.10

Metal binding

189

1

Calcium 1; via carbonyl oxygen

Metal binding

191

1

Calcium 1; via carbonyl oxygen

Metal binding

193

1

Calcium 1

Metal binding

195

1

Zinc 1 Ref.10

Metal binding

197

1

Calcium 2 Ref.10

Metal binding

200

1

Calcium 2 Ref.10

Metal binding

217

1

Zinc 2; catalytic Ref.10

Metal binding

221

1

Zinc 2; catalytic Ref.10

Metal binding

227

1

Zinc 2; catalytic Ref.10

Metal binding

286

1

Calcium 3; via carbonyl oxygen By similarity

Metal binding

378

1

Calcium 3; via carbonyl oxygen By similarity

Metal binding

425

1

Calcium 3; via carbonyl oxygen By similarity

Amino acid modifications

Glycosylation

54

1

N-linked (GlcNAc...) Probable

Glycosylation

73

1

N-linked (GlcNAc...) Probable

Glycosylation

112

1

N-linked (GlcNAc...)

Glycosylation

204

1

N-linked (GlcNAc...) Potential

Glycosylation

246

1

N-linked (GlcNAc...) Potential

Disulfide bond

279 ↔ 464

Probable

Natural variations

Natural variant

3

1

S → C. Ref.2
Corresponds to variant rs17099450 [ dbSNP | Ensembl ].

VAR_025036

Natural variant

32

1

T → I. Ref.2 Ref.4
Corresponds to variant rs3765620 [ dbSNP | Ensembl ].

VAR_025037

Natural variant

87

1

K → E. Ref.2
Corresponds to variant rs1940475 [ dbSNP | Ensembl ].

VAR_006730

Natural variant

154

1

G → E. Ref.2
Corresponds to variant rs35056226 [ dbSNP | Ensembl ].

VAR_025038

Natural variant

193

1

D → V. Ref.2
Corresponds to variant rs34428739 [ dbSNP | Ensembl ].

VAR_025039

Natural variant

246

1

N → Y. Ref.2
Corresponds to variant rs35243553 [ dbSNP | Ensembl ].

VAR_025040

Natural variant

436

1

V → A. Ref.2
Corresponds to variant rs34009635 [ dbSNP | Ensembl ].

VAR_025041

Natural variant

460

1

K → T. Ref.2
Corresponds to variant rs35866072 [ dbSNP | Ensembl ].

VAR_025042

Experimental info

Sequence conflict

40

1

F → I AA sequence Ref.4

Sequence conflict

48

1

Y → V AA sequence Ref.4

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

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.

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.

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.

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.

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.

.

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467

Helix Strand Turn

Details...

Beta strand

107 – 109

3

Beta strand

111 – 117

7

Beta strand

122 – 124

3

Helix

126 – 141

16

Beta strand

147 – 150

4

Beta strand

152 – 154

3

Beta strand

157 – 163

7

Beta strand

168 – 170

3

Beta strand

175 – 178

4

Beta strand

181 – 183

3

Beta strand

186 – 188

3

Turn

189 – 192

4

Beta strand

194 – 197

4

Beta strand

203 – 208

6

Helix

211 – 223

13

Beta strand

236 – 238

3

Beta strand

244 – 246

3

Helix

251 – 261

11

Sequences

	Sequence		Length	Mass (Da)
	P22894 [UniParc]. Last modified August 1, 1991. Version 1. Checksum: 4D4602A53AD7F8BC	FASTA	467	53,412
	10 20 30 40 50 60 MFSLKTLPFL LLLHVQISKA FPVSSKEKNT KTVQDYLEKF YQLPSNQYQS TRKNGTNVIV 70 80 90 100 110 120 EKLKEMQRFF GLNVTGKPNE ETLDMMKKPR CGVPDSGGFM LTPGNPKWER TNLTYRIRNY 130 140 150 160 170 180 TPQLSEAEVE RAIKDAFELW SVASPLIFTR ISQGEADINI AFYQRDHGDN SPFDGPNGIL 190 200 210 220 230 240 AHAFQPGQGI GGDAHFDAEE TWTNTSANYN LFLVAAHEFG HSLGLAHSSD PGALMYPNYA 250 260 270 280 290 300 FRETSNYSLP QDDIDGIQAI YGLSSNPIQP TGPSTPKPCD PSLTFDAITT LRGEILFFKD 310 320 330 340 350 360 RYFWRRHPQL QRVEMNFISL FWPSLPTGIQ AAYEDFDRDL IFLFKGNQYW ALSGYDILQG 370 380 390 400 410 420 YPKDISNYGF PSSVQAIDAA VFYRSKTYFF VNDQFWRYDN QRQFMEPGYP KSISGAFPGI 430 440 450 460 ESKVDAVFQQ EHFFHVFSGP RYYAFDLIAQ RVTRVARGNK WLNCRYG

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Human neutrophil collagenase. A distinct gene product with homology to other matrix metalloproteinases." Hasty K.A., Pourmotabbed T.F., Goldberg G.I., Thompson J.P., Spinella D.G., Stevens R.M., Mainardi C.L. J. Biol. Chem. 265:11421-11424(1990) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 314-337; 347-363 AND 424-441. Tissue: Neutrophil.
[2]	NIEHS SNPs program Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS CYS-3; ILE-32; GLU-87; GLU-154; VAL-193; TYR-246; ALA-436 AND THR-460.
[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]. Tissue: Lung.
[4]	"Characterization and activation of procollagenase from human polymorphonuclear leucocytes. N-terminal sequence determination of the proenzyme and various proteolytically activated forms." Knaeuper V., Kraemer S., Reinke H., Tschesche H. Eur. J. Biochem. 189:295-300(1990) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 21-140, VARIANT ILE-32. Tissue: Neutrophil.
[5]	"Mercurial activation of human polymorphonuclear leucocyte procollagenase." Blaeser J., Knaeuper V., Osthues A., Reinke H., Tschesche H. Eur. J. Biochem. 202:1223-1230(1991) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 21-103. Tissue: Neutrophil.
[6]	"Characterization of 58-kilodalton human neutrophil collagenase: comparison with human fibroblast collagenase." Mallya S.K., Mookthiar K.A., Gao Y., Brew K., Dioszegi M., Birkedal-Hansen H., van Wart H.E. Biochemistry 29:10628-10634(1990) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 85-120, CHARACTERIZATION. Tissue: Neutrophil.
[7]	"Partial amino acid sequence of human PMN leukocyte procollagenase." Knaeuper V., Kraemer S., Reinke H., Tschesche H. Biol. Chem. Hoppe-Seyler 371:295-304(1990) [PubMed] [Europe PMC] [Abstract] Cited for: PARTIAL PROTEIN SEQUENCE.
[8]	Erratum Knaeuper V., Kraemer S., Reinke H., Tschesche H. Biol. Chem. Hoppe-Seyler 371:733-733(1990) [PubMed] [Europe PMC] [Abstract]
[9]	"Formation of a covalent Hg-Cys-bond during mercurial activation of PMNL procollagenase gives evidence of a cysteine-switch mechanism." Blaeser J., Triebel S., Reinke H., Tschesche H. FEBS Lett. 313:59-61(1992) [PubMed] [Europe PMC] [Abstract] Cited for: CYSTEINE-SWITCH MECHANISM. Tissue: Neutrophil.
[10]	"The X-ray crystal structure of the catalytic domain of human neutrophil collagenase inhibited by a substrate analogue reveals the essentials for catalysis and specificity." Bode W., Reinemer P., Huber R., Klein T., Schnierer S., Tschesche H. EMBO J. 13:1263-1269(1994) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 100-262.
[11]	"Structural implications for the role of the N-terminus in the 'superactivation' of collagenases. A crystallographic study." Reinemer P., Grams F., Huber R., Kleine T., Schnierer S., Piper M., Tschesche H., Bode W. FEBS Lett. 338:227-233(1994) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 100-262.
[12]	"Structure of human neutrophil collagenase reveals large S1' specificity pocket." Stams T., Spurlino J.C., Smith D.L., Wahl R.C., Ho T.F., Qoronfleh M.W., Banks T.M., Rubin B. Nat. Struct. Biol. 1:119-123(1994) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 100-262.
[13]	"1.8-A crystal structure of the catalytic domain of human neutrophil collagenase (matrix metalloproteinase-8) complexed with a peptidomimetic hydroxamate primed-side inhibitor with a distinct selectivity profile." Betz M., Huxley P., Davies S.J., Mushtaq Y., Pieper M., Tschesche H., Bode W., Gomis-Rueth F.-X. Eur. J. Biochem. 247:356-363(1997) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.81 ANGSTROMS) OF 100-262.
[14]	"Structure of malonic acid-based inhibitors bound to human neutrophil collagenase. A new binding mode explains apparently anomalous data." Brandstetter H., Engh R.A., von Roedern E.G., Moroder L., Huber R., Bode W., Grams F. Protein Sci. 7:1303-1309(1998) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 105-262.
+	Additional computationally mapped references.

Web resources

NIEHS-SNPs

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

J05556 mRNA. Translation: AAA88021.1.
DQ141306 Genomic DNA. Translation: AAZ38714.1.
BC074988 mRNA. Translation: AAH74988.1.
BC074989 mRNA. Translation: AAH74989.1.

IPI

IPI00027846.

PIR

KCHUN. A37073.

RefSeq

NP_002415.1. NM_002424.2.

UniGene

Hs.161839.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1A85	X-ray	2.00	A	105-262	[»]
1A86	X-ray	2.00	A	105-262	[»]
1BZS	X-ray	1.70	A	99-262	[»]
1I73	X-ray	1.40	A	100-262	[»]
1I76	X-ray	1.20	A	100-262	[»]
1JAN	X-ray	2.50	A	99-262	[»]
1JAO	X-ray	2.40	A	100-262	[»]
1JAP	X-ray	1.82	A	100-262	[»]
1JAQ	X-ray	2.40	A	100-262	[»]
1JH1	X-ray	2.70	A	105-262	[»]
1JJ9	X-ray	2.00	A	100-262	[»]
1KBC	X-ray	1.80	A/B	99-262	[»]
1MMB	X-ray	2.10	A	100-262	[»]
1MNC	X-ray	2.10	A	101-263	[»]
1ZP5	X-ray	1.80	A	100-262	[»]
1ZS0	X-ray	1.56	A	100-262	[»]
1ZVX	X-ray	1.87	A	100-262	[»]
2OY2	X-ray	1.50	A/F	105-262	[»]
2OY4	X-ray	1.70	A/F	105-262	[»]
3DNG	X-ray	2.00	A/B	100-262	[»]
3DPE	X-ray	1.60	A	100-262	[»]
3DPF	X-ray	2.10	A/B	100-262	[»]
3TT4	X-ray	1.88	A	104-262	[»]

ProteinModelPortal

P22894.

ModBase

Search...

Protein-protein interaction databases

STRING

9606.ENSP00000236826.

Protein family/group databases

MEROPS

M10.002.

PTM databases

PhosphoSite

P22894.

Polymorphism databases

DMDM

116862.

Proteomic databases

PaxDb

P22894.

PeptideAtlas

P22894.

PRIDE

P22894.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000236826; ENSP00000236826; ENSG00000118113.

GeneID

4317.

KEGG

hsa:4317.

UCSC

uc001phe.2. human.

Organism-specific databases

CTD

4317.

GeneCards

GC11M102617.

HGNC

HGNC:7175. MMP8.

HPA

HPA021221.
HPA022935.

MIM

120355. gene.

neXtProt

NX_P22894.

PharmGKB

PA30888.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG258253.

HOGENOM

HOG000217927.

HOVERGEN

HBG052484.

InParanoid

P22894.

KO

K01402.

OMA

SNRWLNC.

OrthoDB

EOG4X97GX.

PhylomeDB

P22894.

Enzyme and pathway databases

Reactome

REACT_118779. Extracellular matrix organization.

Gene expression databases

ArrayExpress

P22894.

Bgee

P22894.

CleanEx

HS_MMP8.

Genevestigator

P22894.

GermOnline

ENSG00000118113. Homo sapiens.

Family and domain databases

Gene3D

2.110.10.10. 1 hit.
3.40.390.10. 1 hit.

InterPro

IPR000585. Hemopexin-like_dom.
IPR018487. Hemopexin-like_repeat.
IPR018486. Hemopexin_CS.
IPR024079. MetalloPept_cat_dom.
IPR001818. Pept_M10_metallopeptidase.
IPR021190. Pept_M10A.
IPR016293. Pept_M10A_Metazoans.
IPR021158. Pept_M10A_Zn_BS.
IPR006026. Peptidase_Metallo.
IPR002477. Peptidoglycan-bd-like.
[Graphical view]

Pfam

PF00045. Hemopexin. 4 hits.
PF00413. Peptidase_M10. 1 hit.
PF01471. PG_binding_1. 1 hit.
[Graphical view]

PIRSF

PIRSF001191. Peptidase_M10A_matrix. 1 hit.

PRINTS

PR00138. MATRIXIN.

SMART

SM00120. HX. 4 hits.
SM00235. ZnMc. 1 hit.
[Graphical view]

SUPFAM

SSF50923. Hemopexin. 1 hit.
SSF47090. PGBD_like. 1 hit.

PROSITE

PS00546. CYSTEINE_SWITCH. 1 hit.
PS00024. HEMOPEXIN. 1 hit.
PS00142. ZINC_PROTEASE. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P22894.

ChEMBL

CHEMBL4588.

EvolutionaryTrace

P22894.

GenomeRNAi

4317.

NextBio

16985.

PMAP-CutDB

P22894.

SOURCE

Search...

Entry information

Entry name

MMP8_HUMAN

Accession

Primary (citable) accession number: P22894
Secondary accession number(s): Q45F99

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 1, 1991
Last sequence update:	August 1, 1991
Last modified:	May 1, 2013
This is version 143 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.