P08253 (MMP2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
72 kDa type IV collagenase
EC=3.4.24.24

Alternative name(s):
72 kDa gelatinase
Gelatinase A
Matrix metalloproteinase-2
Short name=MMP-2
TBE-1

Cleaved into the following chain:

1. PEX

Gene names

Name:	MMP2
Synonyms:	CLG4A

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	660 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	Ubiquitinous metalloproteinase that is involved in diverse functions such as remodeling of the vasculature, angiogenesis, tissue repair, tumor invasion, inflammation, and atherosclerotic plaque rupture. As well as degrading extracellular matrix proteins, can also act on several nonmatrix proteins such as big endothelial 1 and beta-type CGRP promoting vasoconstriction. Also cleaves KISS at a Gly-|-Leu bond. Appears to have a role in myocardial cell death pathways. Contributes to myocardial oxidative stress by regulating the activity of GSK3beta. Cleaves GSK3beta in vitro. Ref.13 Ref.14 Ref.15 Ref.16 Ref.18 Ref.22 Ref.24 PEX, the C-terminal non-catalytic fragment of MMP2, posseses anti-angiogenic and anti-tumor properties and inhibits cell migration and cell adhesion to FGF2 and vitronectin. Ligand for integrinv/beta3 on the surface of blood vessels. Ref.13 Ref.14 Ref.15 Ref.16 Ref.18 Ref.22 Ref.24 Isoform 2: Mediates the proteolysis of CHUK/IKKA and initiates a primary innate immune response by inducing mitochondrial-nuclear stress signaling with activation of the pro-inflammatory NF-kappaB, NFAT and IRF transcriptional pathways. Ref.13 Ref.14 Ref.15 Ref.16 Ref.18 Ref.22 Ref.24
Catalytic activity	Cleavage of gelatin type I and collagen types IV, V, VII, X. Cleaves the collagen-like sequence Pro-Gln-Gly-|-Ile-Ala-Gly-Gln.
Cofactor	Binds 4 calcium ions per subunit. Binds 2 zinc ions per subunit.
Enzyme regulation	Inhibited by histatin-3 1/24 (histatin-5). Ref.17
Subunit structure	Interacts (via the C-terminal hemopexin-like domains-containing region) with the integrin alpha-V/beta-3; the interaction promotes vascular invasion in angiogenic vessels and melamoma cells. Interacts (via the C-terminal PEX domain) with TIMP2 (via the C-terminal); the interaction inhibits the degradation activity. Interacts with GSK3B. Ref.10 Ref.16 Ref.18 Ref.22
Subcellular location	Isoform 1: Secreted › extracellular space › extracellular matrix. Membrane. Nucleus. Note: Colocalizes with integrin alphaV/beta3 at the membrane surface in angiogenic blood vessels and melanomas. Found in mitochondria, along microfibrils, and in nuclei of cardiomyocytes. Ref.11 Ref.20 Ref.24 Isoform 2: Cytoplasm. Mitochondrion Ref.11 Ref.20 Ref.24.
Tissue specificity	Produced by normal skin fibroblasts. PEX is expressed in a number of tumors including gliomas, breast and prostate. Ref.16
Induction	Aspirin appears to inhibit expression. Ref.17 Ref.23
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.
Post-translational modification	Phosphorylation on multiple sites modulates enzymatic activity. Phosphorylated by PKC in vitro. Ref.21 The propeptide is processed by MMP14 (MT-MMP1) and MMP16 (MT-MMP3). Autocatalytic cleavage in the C-terminal produces the anti-angiogenic peptide, PEX. This processing appears to be facilitated by binding integrinv/beta3.
Involvement in disease	Torg-Winchester syndrome (TWS) [MIM:259600]: An autosomal recessive syndrome characterized by severe multicentric osteolysis with predominant involvement of the hands and feet. Additional features include coarse face, corneal opacities, patches of thickened, hyperpigmented skin, hypertrichosis and gum hypertrophy. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.34 Ref.35 Ref.36
Sequence similarities	Belongs to the peptidase M10A family. Contains 3 fibronectin type-II domains. Contains 4 hemopexin-like domains.

Ontologies

Keywords
Biological process	Angiogenesis Collagen degradation
Cellular component	Cytoplasm Extracellular matrix Membrane Mitochondrion Nucleus Secreted
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Domain	Repeat Signal
Ligand	Calcium Metal-binding Zinc
Molecular function	Hydrolase Metalloprotease Protease
PTM	Autocatalytic cleavage Disulfide bond Glycoprotein Phosphoprotein Zymogen
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	angiogenesis Inferred from electronic annotation. Source: UniProtKB-KW blood vessel maturation Inferred from electronic annotation. Source: Compara bone trabecula formation Inferred from electronic annotation. Source: Compara cellular response to amino acid stimulus Inferred from electronic annotation. Source: Compara collagen catabolic process Inferred from electronic annotation. Source: UniProtKB-KW embryo implantation Inferred from electronic annotation. Source: Compara extracellular matrix disassembly Traceable author statement. Source: Reactome face morphogenesis Inferred from electronic annotation. Source: Compara intramembranous ossification Inferred from electronic annotation. Source: Compara proteolysis Traceable author statement Ref.8. Source: ProtInc response to hypoxia Inferred from electronic annotation. Source: Compara
Cellular_component	extracellular space Inferred from direct assay PubMed 20551380. Source: BHF-UCL mitochondrion Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell plasma membrane Inferred from electronic annotation. Source: Compara proteinaceous extracellular matrix Inferred from electronic annotation. Source: UniProtKB-SubCell sarcomere Inferred from electronic annotation. Source: Compara
Molecular_function	metalloendopeptidase activity Traceable author statement Ref.8. Source: ProtInc serine-type endopeptidase activity Traceable author statement. Source: Reactome zinc ion binding Traceable author statement Ref.8. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
SCUBE3	Q8IX30	2	EBI-1033518,EBI-4479975

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P08253-1)

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: P08253-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-76: Missing.

Note: Induced by oxidative stress.

Isoform 3 (identifier: P08253-3)

The sequence of this isoform differs from the canonical sequence as follows:
     1-51: MEALMARGALTGPLRALCLLGCLLSHAAAAPSPIIKFPGDVAPKTDKELAV → M

Note: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 29

29

Potential

Propeptide

30 – 109

80

Activation peptide

PRO_0000028714

Chain

110 – 660

551

72 kDa type IV collagenase

PRO_0000028715

Chain

445 – 660

216

PEX

PRO_0000391626

Regions

Domain

228 – 276

49

Fibronectin type-II 1

Domain

286 – 334

49

Fibronectin type-II 2

Domain

344 – 392

49

Fibronectin type-II 3

Domain

475 – 518

44

Hemopexin-like 1

Domain

520 – 563

44

Hemopexin-like 2

Domain

568 – 615

48

Hemopexin-like 3

Domain

617 – 660

44

Hemopexin-like 4

Region

110 – 221

112

Collagenase-like 1

Region

222 – 396

175

Collagen-binding

Region

397 – 465

69

Collagenase-like 2

Region

414 – 660

247

Required for inhibitor TIMP2 binding

Motif

100 – 107

8

Cysteine switch By similarity

Sites

Active site

404

1

By similarity

Metal binding

102

1

Zinc 2; in inhibited form By similarity

Metal binding

134

1

Calcium 1 By similarity

Metal binding

168

1

Calcium 2 By similarity

Metal binding

178

1

Zinc 1 By similarity

Metal binding

180

1

Zinc 1 By similarity

Metal binding

185

1

Calcium 3 By similarity

Metal binding

186

1

Calcium 3; via carbonyl oxygen By similarity

Metal binding

193

1

Zinc 1 By similarity

Metal binding

200

1

Calcium 2; via carbonyl oxygen By similarity

Metal binding

202

1

Calcium 2; via carbonyl oxygen By similarity

Metal binding

204

1

Calcium 2 By similarity

Metal binding

206

1

Zinc 1 By similarity

Metal binding

208

1

Calcium 3 By similarity

Metal binding

209

1

Calcium 1 By similarity

Metal binding

211

1

Calcium 3 By similarity

Metal binding

403

1

Zinc 2; catalytic By similarity

Metal binding

407

1

Zinc 2; catalytic By similarity

Metal binding

413

1

Zinc 2; catalytic By similarity

Metal binding

476

1

Calcium 4; via carbonyl oxygen

Metal binding

521

1

Calcium 4; via carbonyl oxygen

Metal binding

569

1

Calcium 4; via carbonyl oxygen

Metal binding

618

1

Calcium 4; via carbonyl oxygen

Amino acid modifications

Glycosylation

573

1

N-linked (GlcNAc...) Potential

Glycosylation

642

1

N-linked (GlcNAc...) Potential

Disulfide bond

233 ↔ 259

By similarity

Disulfide bond

247 ↔ 274

By similarity

Disulfide bond

291 ↔ 317

By similarity

Disulfide bond

305 ↔ 332

By similarity

Disulfide bond

349 ↔ 375

By similarity

Disulfide bond

363 ↔ 390

By similarity

Disulfide bond

469 ↔ 660

Ref.28

Natural variations

Alternative sequence

1 – 76

76

Missing in isoform 2.

VSP_044631

Alternative sequence

1 – 51

51

MEALM…KELAV → M in isoform 3.

VSP_045704

Natural variant

101

1

R → H in TWS. Ref.34

VAR_032423

Natural variant

210

1

D → Y. Ref.34

VAR_032424

Natural variant

228

1

A → T in a colorectal cancer sample; somatic mutation. Ref.37

VAR_036136

Natural variant

400

1

Missing in TWS. Ref.36

VAR_054996

Natural variant

404

1

E → K in TWS. Ref.35

VAR_032425

Natural variant

447

1

A → V. Ref.4
Corresponds to variant rs17859943 [ dbSNP | Ensembl ].

VAR_020616

Natural variant

498

1

T → M in a colorectal cancer sample; somatic mutation. Ref.37

VAR_036137

Natural variant

621

1

V → L. Ref.4
Corresponds to variant rs16955280 [ dbSNP | Ensembl ].

VAR_020617

Natural variant

644

1

S → I in a colorectal cancer sample; somatic mutation. Ref.37

VAR_036138

Experimental info

Sequence conflict

235

1

F → S in AK310314. Ref.3

Sequence conflict

546

1

S → G in BAG35588. Ref.3

Sequence conflict

618

1

D → G in BAG35588. Ref.3

Secondary structure

1

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660

Helix Strand Turn

Details...

Helix

46 – 56

11

Turn

62 – 64

3

Helix

67 – 80

14

Beta strand

86 – 88

3

Helix

91 – 97

7

Beta strand

111 – 113

3

Beta strand

120 – 128

9

Beta strand

133 – 135

3

Helix

137 – 152

16

Beta strand

154 – 156

3

Beta strand

158 – 161

4

Beta strand

163 – 165

3

Beta strand

168 – 174

7

Beta strand

179 – 181

3

Beta strand

186 – 189

4

Beta strand

192 – 195

4

Beta strand

197 – 199

3

Turn

200 – 203

4

Beta strand

205 – 208

4

Beta strand

209 – 211

3

Beta strand

213 – 216

4

Helix

226 – 228

3

Beta strand

235 – 239

5

Beta strand

242 – 246

5

Beta strand

258 – 264

7

Turn

265 – 267

3

Beta strand

271 – 273

3

Turn

277 – 279

3

Turn

284 – 288

5

Beta strand

293 – 297

5

Beta strand

300 – 304

5

Beta strand

316 – 321

6

Turn

323 – 325

3

Beta strand

329 – 331

3

Beta strand

338 – 341

4

Turn

342 – 346

5

Beta strand

351 – 355

5

Beta strand

358 – 362

5

Beta strand

369 – 371

3

Beta strand

374 – 379

6

Helix

381 – 384

4

Beta strand

387 – 389

3

Beta strand

394 – 396

3

Helix

397 – 408

12

Beta strand

422 – 424

3

Helix

435 – 445

11

Turn

468 – 470

3

Beta strand

476 – 481

6

Beta strand

484 – 489

6

Beta strand

492 – 498

7

Beta strand

504 – 508

5

Helix

509 – 511

3

Beta strand

514 – 516

3

Beta strand

521 – 526

6

Turn

527 – 530

4

Beta strand

531 – 536

6

Beta strand

539 – 544

6

Beta strand

553 – 555

3

Helix

556 – 559

4

Turn

563 – 566

4

Beta strand

569 – 573

5

Turn

575 – 577

3

Beta strand

580 – 584

5

Beta strand

587 – 592

6

Turn

593 – 596

4

Helix

606 – 609

4

Beta strand

610 – 612

3

Beta strand

618 – 622

5

Turn

624 – 626

3

Beta strand

628 – 633

6

Beta strand

636 – 641

6

Beta strand

644 – 652

9

Helix

653 – 656

4

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified February 1, 1991. Version 2. Checksum: BC7147DC8B49F289	FASTA	660	73,882
	10 20 30 40 50 60 MEALMARGAL TGPLRALCLL GCLLSHAAAA PSPIIKFPGD VAPKTDKELA VQYLNTFYGC 70 80 90 100 110 120 PKESCNLFVL KDTLKKMQKF FGLPQTGDLD QNTIETMRKP RCGNPDVANY NFFPRKPKWD 130 140 150 160 170 180 KNQITYRIIG YTPDLDPETV DDAFARAFQV WSDVTPLRFS RIHDGEADIM INFGRWEHGD 190 200 210 220 230 240 GYPFDGKDGL LAHAFAPGTG VGGDSHFDDD ELWTLGEGQV VRVKYGNADG EYCKFPFLFN 250 260 270 280 290 300 GKEYNSCTDT GRSDGFLWCS TTYNFEKDGK YGFCPHEALF TMGGNAEGQP CKFPFRFQGT 310 320 330 340 350 360 SYDSCTTEGR TDGYRWCGTT EDYDRDKKYG FCPETAMSTV GGNSEGAPCV FPFTFLGNKY 370 380 390 400 410 420 ESCTSAGRSD GKMWCATTAN YDDDRKWGFC PDQGYSLFLV AAHEFGHAMG LEHSQDPGAL 430 440 450 460 470 480 MAPIYTYTKN FRLSQDDIKG IQELYGASPD IDLGTGPTPT LGPVTPEICK QDIVFDGIAQ 490 500 510 520 530 540 IRGEIFFFKD RFIWRTVTPR DKPMGPLLVA TFWPELPEKI DAVYEAPQEE KAVFFAGNEY 550 560 570 580 590 600 WIYSASTLER GYPKPLTSLG LPPDVQRVDA AFNWSKNKKT YIFAGDKFWR YNEVKKKMDP 610 620 630 640 650 660 GFPKLIADAW NAIPDNLDAV VDLQGGGHSY FFKGAYYLKL ENQSLKSVKF GSIKSDWLGC
	Isoform 2 [UniParc]. Checksum: EC1C16C91ECBC26C	FASTA	584	65,765
	10 20 30 40 50 60 MQKFFGLPQT GDLDQNTIET MRKPRCGNPD VANYNFFPRK PKWDKNQITY RIIGYTPDLD 70 80 90 100 110 120 PETVDDAFAR AFQVWSDVTP LRFSRIHDGE ADIMINFGRW EHGDGYPFDG KDGLLAHAFA 130 140 150 160 170 180 PGTGVGGDSH FDDDELWTLG EGQVVRVKYG NADGEYCKFP FLFNGKEYNS CTDTGRSDGF 190 200 210 220 230 240 LWCSTTYNFE KDGKYGFCPH EALFTMGGNA EGQPCKFPFR FQGTSYDSCT TEGRTDGYRW 250 260 270 280 290 300 CGTTEDYDRD KKYGFCPETA MSTVGGNSEG APCVFPFTFL GNKYESCTSA GRSDGKMWCA 310 320 330 340 350 360 TTANYDDDRK WGFCPDQGYS LFLVAAHEFG HAMGLEHSQD PGALMAPIYT YTKNFRLSQD 370 380 390 400 410 420 DIKGIQELYG ASPDIDLGTG PTPTLGPVTP EICKQDIVFD GIAQIRGEIF FFKDRFIWRT 430 440 450 460 470 480 VTPRDKPMGP LLVATFWPEL PEKIDAVYEA PQEEKAVFFA GNEYWIYSAS TLERGYPKPL 490 500 510 520 530 540 TSLGLPPDVQ RVDAAFNWSK NKKTYIFAGD KFWRYNEVKK KMDPGFPKLI ADAWNAIPDN 550 560 570 580 LDAVVDLQGG GHSYFFKGAY YLKLENQSLK SVKFGSIKSD WLGC
	Isoform 3 [UniParc]. Checksum: FB214CA4334DC5FC	FASTA	610	68,831
	10 20 30 40 50 60 MQYLNTFYGC PKESCNLFVL KDTLKKMQKF FGLPQTGDLD QNTIETMRKP RCGNPDVANY 70 80 90 100 110 120 NFFPRKPKWD KNQITYRIIG YTPDLDPETV DDAFARAFQV WSDVTPLRFS RIHDGEADIM 130 140 150 160 170 180 INFGRWEHGD GYPFDGKDGL LAHAFAPGTG VGGDSHFDDD ELWTLGEGQV VRVKYGNADG 190 200 210 220 230 240 EYCKFPFLFN GKEYNSCTDT GRSDGFLWCS TTYNFEKDGK YGFCPHEALF TMGGNAEGQP 250 260 270 280 290 300 CKFPFRFQGT SYDSCTTEGR TDGYRWCGTT EDYDRDKKYG FCPETAMSTV GGNSEGAPCV 310 320 330 340 350 360 FPFTFLGNKY ESCTSAGRSD GKMWCATTAN YDDDRKWGFC PDQGYSLFLV AAHEFGHAMG 370 380 390 400 410 420 LEHSQDPGAL MAPIYTYTKN FRLSQDDIKG IQELYGASPD IDLGTGPTPT LGPVTPEICK 430 440 450 460 470 480 QDIVFDGIAQ IRGEIFFFKD RFIWRTVTPR DKPMGPLLVA TFWPELPEKI DAVYEAPQEE 490 500 510 520 530 540 KAVFFAGNEY WIYSASTLER GYPKPLTSLG LPPDVQRVDA AFNWSKNKKT YIFAGDKFWR 550 560 570 580 590 600 YNEVKKKMDP GFPKLIADAW NAIPDNLDAV VDLQGGGHSY FFKGAYYLKL ENQSLKSVKF 610 GSIKSDWLGC

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Structure of the human type IV collagenase gene." Huhtala P., Chow L.T., Tryggvason K. J. Biol. Chem. 265:11077-11082(1990) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[2]	"On the structure and chromosome location of the 72- and 92-kDa human type IV collagenase genes." Collier I.E., Bruns G.A.P., Goldberg G.I., Gerhard D.S. Genomics 9:429-434(1991) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 3). Tissue: Teratocarcinoma and Testis.
[4]	NIEHS SNPs program Submitted (AUG-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS VAL-447 AND LEU-621.
[5]	"The sequence and analysis of duplication-rich human chromosome 16." Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J. , Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J., Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D., Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M., Rubin E.M., Pennacchio L.A. Nature 432:988-994(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"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] (ISOFORM 1). Tissue: Brain.
[7]	"Completion of the primary structure of the human type IV collagenase preproenzyme and assignment of the gene (CLG4) to the q21 region of chromosome 16." Huhtala P., Eddy R.L., Fan Y.S., Byers M.G., Shows T.B., Tryggvason K. Genomics 6:554-559(1990) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-51.
[8]	"H-ras oncogene-transformed human bronchial epithelial cells (TBE-1) secrete a single metalloprotease capable of degrading basement membrane collagen." Collier I.E., Wilhelm S.M., Eisen A.Z., Marmer B.L., Grant G.A., Seltzer J.L., Kronberger A., He C., Bauer E.A., Goldberg G.I. J. Biol. Chem. 263:6579-6587(1988) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 19-660 (ISOFORM 1), PARTIAL PROTEIN SEQUENCE.
[9]	"TIMP-2: identification and characterization of a new member of the metalloproteinase inhibitor family." Stetler-Stevenson W.G., Krutzsch H.C., Liotta L.A. Matrix Suppl. 1:299-306(1992) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 30-44. Tissue: Melanoma.
[10]	"Binding of tissue inhibitor of metalloproteinases 2 to two distinct sites on human 72-kDa gelatinase. Identification of a stabilization site." Howard E.W., Banda M.J. J. Biol. Chem. 266:17972-17977(1991) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH TIMP2.
[11]	"Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3." Brooks P.C., Stroemblad S., Sanders L.C., von Schalscha T.L., Aimes R.T., Stetler-Stevenson W.G., Quigley J.P., Cheresh D.A. Cell 85:683-693(1996) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION OF RECEPTOR, SUBCELLULAR LOCATION.
[12]	"Membrane-type-2 matrix metalloproteinase can initiate the processing of progelatinase A and is regulated by the tissue inhibitors of metalloproteinases." Butler G.S., Will H., Atkinson S.J., Murphy G. Eur. J. Biochem. 244:653-657(1997) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEOLYTIC PROCESSING.
[13]	"Disruption of angiogenesis by PEX, a noncatalytic metalloproteinase fragment with integrin binding activity." Brooks P.C., Silletti S., von Schalscha T.L., Friedlander M., Cheresh D.A. Cell 92:391-400(1998) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION OF RECEPTOR, FUNCTION.
[14]	"Vascular matrix metalloproteinase-2 cleaves big endothelin-1 yielding a novel vasoconstrictor." Fernandez-Patron C., Radomski M.W., Davidge S.T. Circ. Res. 85:906-911(1999) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[15]	"Vascular matrix metalloproteinase-2-dependent cleavage of calcitonin gene-related peptide promotes vasoconstriction." Fernandez-Patron C., Stewart K.G., Zhang Y., Koivunen E., Radomski M.W., Davidge S.T. Circ. Res. 87:670-676(2000) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[16]	"Simultaneous inhibition of glioma angiogenesis, cell proliferation, and invasion by a naturally occurring fragment of human metalloproteinase-2." Bello L., Lucini V., Carrabba G., Giussani C., Machluf M., Pluderi M., Nikas D., Zhang J., Tomei G., Villani R.M., Carroll R.S., Bikfalvi A., Black P.M. Cancer Res. 61:8730-8736(2001) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION OF PEX, TISSUE SPECIFICITY, INTERACTION WITH TIMP2.
[17]	"Salivary histatin 5 is an inhibitor of both host and bacterial enzymes implicated in periodontal disease." Gusman H., Travis J., Helmerhorst E.J., Potempa J., Troxler R.F., Oppenheim F.G. Infect. Immun. 69:1402-1408(2001) [PubMed] [Europe PMC] [Abstract] Cited for: ENZYME REGULATION.
[18]	"Human cervical tumor cell (SiHa) surface alphavbeta3 integrin receptor has associated matrix metalloproteinase (MMP-2) activity." Chattopadhyay N., Mitra A., Frei E., Chatterjee A. J. Cancer Res. Clin. Oncol. 127:653-658(2001) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION OF RECEPTOR, INTERACTION WITH TMP2, FUNCTION.
[19]	"Cleavage of metastasis suppressor gene product KiSS-1 protein/metastin by matrix metalloproteinases." Takino T., Koshikawa N., Miyamori H., Tanaka M., Sasaki T., Okada Y., Seiki M., Sato H. Oncogene 22:4617-4626(2003) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEOLYTIC PROCESSING OF KISS1.
[20]	"Matrix metalloproteinase-2 (MMP-2) is present in the nucleus of cardiac myocytes and is capable of cleaving poly (ADP-ribose) polymerase (PARP) in vitro." Kwan J.A., Schulze C.J., Wang W., Leon H., Sariahmetoglu M., Sung M., Sawicka J., Sims D.E., Sawicki G., Schulz R. FASEB J. 18:690-692(2004) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION.
[21]	"Regulation of matrix metalloproteinase-2 (MMP-2) activity by phosphorylation." Sariahmetoglu M., Crawford B.D., Leon H., Sawicka J., Li L., Ballermann B.J., Holmes C., Berthiaume L.G., Holt A., Sawicki G., Schulz R. FASEB J. 21:2486-2495(2007) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION, MASS SPECTROMETRY.
[22]	"Glycogen synthase kinase-3beta is activated by matrix metalloproteinase-2 mediated proteolysis in cardiomyoblasts." Kandasamy A.D., Schulz R. Cardiovasc. Res. 83:698-706(2009) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH GSK3B, FUNCTION.
[23]	"Aspirin inhibits MMP-2 and MMP-9 expressions and activities through upregulation of PPARalpha/gamma and TIMP gene expressions in ox-LDL-stimulated macrophages derived from human monocytes." Hua Y., Xue J., Sun F., Zhu L., Xie M. Pharmacology 83:18-25(2009) [PubMed] [Europe PMC] [Abstract] Cited for: INDUCTION.
[24]	"A novel intracellular isoform of matrix metalloproteinase-2 induced by oxidative stress activates innate immunity." Lovett D.H., Mahimkar R., Raffai R.L., Cape L., Maklashina E., Cecchini G., Karliner J.S. PLoS ONE 7:E34177-E34177(2012) [PubMed] [Europe PMC] [Abstract] Cited for: ALTERNATIVE SPLICING (ISOFORM 2), FUNCTION, SUBCELLULAR LOCATION.
[25]	"Crystal structure of the haemopexin-like C-terminal domain of gelatinase A." Libson A.M., Gittis A.G., Collier I.E., Marmer B.L., Goldberg G.I., Lattman E.E. Nat. Struct. Biol. 2:938-942(1995) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.15 ANGSTROMS) OF 443-660.
[26]	"The C-terminal (haemopexin-like) domain structure of human gelatinase A (MMP2): structural implications for its function." Gohlke U., Gomis-Rueth F.-X., Crabbe T., Murphy G., Docherty A.J., Bode W. FEBS Lett. 378:126-130(1996) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 458-660.
[27]	"Structure of human pro-matrix metalloproteinase-2: activation mechanism revealed." Morgunova E., Tuuttila A., Bergmann U., Isupov M., Lindqvist Y., Schneider G., Tryggvason K. Science 284:1667-1670(1999) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 30-660 OF MUTANT ALA-404.
[28]	"The second type II module from human matrix metalloproteinase 2: structure, function and dynamics." Briknarova K., Grishaev A., Banyai L., Tordai H., Patthy L., Llinas M. Structure 7:1235-1245(1999) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 278-336, DISULFIDE BONDS.
[29]	"Gelatin-binding region of human matrix metalloproteinase-2: solution structure, dynamics, and function of the COL-23 two-domain construct." Briknarova K., Gehrmann M., Banyai L., Tordai H., Patthy L., Llinas M. J. Biol. Chem. 276:27613-27621(2001) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 337-394 OF WILD TYPE AND IN COMPLEX WITH PPG PEPTIDES.
[30]	"Solution structure and backbone dynamics of the catalytic domain of matrix metalloproteinase-2 complexed with a hydroxamic acid inhibitor." Feng Y., Likos J.J., Zhu L., Woodward H., Munie G., McDonald J.J., Stevens A.M., Howard C.P., De Crescenzo G.A., Welsch D., Shieh H.S., Stallings W.C. Biochim. Biophys. Acta 1598:10-23(2002) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 110-446 IN COMPLEX WITH A HYDROXAMIC ACID INHIBITOR.
[31]	"The col-1 module of human matrix metalloproteinase-2 (MMP-2): structural/functional relatedness between gelatin-binding fibronectin type II modules and lysine-binding kringle domains." Gehrmann M., Briknarova K., Banyai L., Patthy L., Llinas M. Biol. Chem. 383:137-148(2002) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 223-282 OF WILD TYPE AND IN COMPLEX WITH A PPG PEPTIDE.
[32]	"Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2." Morgunova E., Tuuttila A., Bergmann U., Tryggvason K. Proc. Natl. Acad. Sci. U.S.A. 99:7414-7419(2002) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (3.1 ANGSTROMS) OF 30-660 IN COMPLEX WITH INHIBITOR TIMP2.
[33]	"Matrix metalloproteinase target family landscape: a chemometrical approach to ligand selectivity based on protein binding site analysis." Pirard B., Matter H. J. Med. Chem. 49:51-69(2006) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 115-449.
[34]	"Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome." Martignetti J.A., Aqeel A.A., Sewairi W.A., Boumah C.E., Kambouris M., Mayouf S.A., Sheth K.V., Eid W.A., Dowling O., Harris J., Glucksman M.J., Bahabri S., Meyer B.F., Desnick R.J. Nat. Genet. 28:261-265(2001) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT TWS HIS-101, VARIANT TYR-210.
[35]	"Winchester syndrome caused by a homozygous mutation affecting the active site of matrix metalloproteinase 2." Zankl A., Bonafe L., Calcaterra V., Di Rocco M., Superti-Furga A. Clin. Genet. 67:261-266(2005) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT TWS LYS-404.
[36]	"A novel homozygous MMP2 mutation in a family with Winchester syndrome." Rouzier C., Vanatka R., Bannwarth S., Philip N., Coussement A., Paquis-Flucklinger V., Lambert J.-C. Clin. Genet. 69:271-276(2006) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT TWS VAL-400 DEL.
[37]	"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: VARIANTS [LARGE SCALE ANALYSIS] THR-228; MET-498 AND ILE-644.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

NIEHS-SNPs

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M55593 , M58552, M55582, M55583, M55584, M55585, M55586, M55587, M55588, M55589, M55590, M55591, M55592 Genomic DNA. Translation: AAA52028.1.
AK301536 mRNA. Translation: BAG63035.1.
AK310314 mRNA. No translation available.
AK312711 mRNA. Translation: BAG35588.1.
AY738117 Genomic DNA. Translation: AAU10089.1.
AC007336 Genomic DNA. No translation available.
AC092722 Genomic DNA. No translation available.
BC002576 mRNA. Translation: AAH02576.1.
M33789 Genomic DNA. Translation: AAA52027.1.
J03210 mRNA. Translation: AAA35701.1.

IPI

IPI00027780.
IPI00895858.
IPI01009185.

PIR

A28153.

RefSeq

NP_001121363.1. NM_001127891.1.
NP_004521.1. NM_004530.4.

UniGene

Hs.513617.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1CK7	X-ray	2.80	A	30-660	[»]
1CXW	NMR	-	A	278-336	[»]
1EAK	X-ray	2.66	A/B/C/D	32-452	[»]
1GEN	X-ray	2.15	A	443-660	[»]
1GXD	X-ray	3.10	A/B	30-660	[»]
1HOV	NMR	-	A	110-446	[»]
1J7M	NMR	-	A	337-394	[»]
1KS0	NMR	-	A	223-282	[»]
1QIB	X-ray	2.80	A	115-449	[»]
1RTG	X-ray	2.60	A	451-660	[»]
3AYU	X-ray	2.00	A	110-450	[»]

ProteinModelPortal

P08253.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-26N.

IntAct

P08253. 9 interactions.

STRING

9606.ENSP00000219070.

Protein family/group databases

MEROPS

M10.003.

PTM databases

PhosphoSite

P08253.

Polymorphism databases

DMDM

116856.

Proteomic databases

PaxDb

P08253.

PeptideAtlas

P08253.

PRIDE

P08253.

Protocols and materials databases

DNASU

4313.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000219070; ENSP00000219070; ENSG00000087245.
ENST00000437642; ENSP00000394237; ENSG00000087245.
ENST00000543485; ENSP00000444143; ENSG00000087245.
ENST00000570308; ENSP00000461421; ENSG00000087245.

GeneID

4313.

KEGG

hsa:4313.

UCSC

uc002ehz.4. human.

Organism-specific databases

CTD

4313.

GeneCards

GC16P055424.

HGNC

HGNC:7166. MMP2.

HPA

CAB002788.
HPA001939.

MIM

120360. gene.
259600. phenotype.

neXtProt

NX_P08253.

Orphanet

85196. Nodulosis-arthropathy-osteolysis syndrome.
3460. Torg-Winchester syndrome.

PharmGKB

PA30877.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG303159.

HOGENOM

HOG000217926.

HOVERGEN

HBG052484.

InParanoid

P08253.

KO

K01398.

OMA

MINFGRW.

OrthoDB

EOG49CQ74.

PhylomeDB

P08253.

Enzyme and pathway databases

BioCyc

MetaCyc:HS01565-MONOMER.

BRENDA

3.4.24.24. 2681.

Pathway_Interaction_DB

amb2_neutrophils_pathway. amb2 Integrin signaling.
foxm1pathway. FOXM1 transcription factor network.
lysophospholipid_pathway. LPA receptor mediated events.
avb3_opn_pathway. Osteopontin-mediated events.
er_nongenomic_pathway. Plasma membrane estrogen receptor signaling.
syndecan_2_pathway. Syndecan-2-mediated signaling events.

Reactome

REACT_116125. Disease.
REACT_118779. Extracellular matrix organization.
REACT_132934. Extracellular matrix organization.
REACT_133391. Extracellular matrix organization.

Gene expression databases

ArrayExpress

P08253.

Bgee

P08253.

CleanEx

HS_MMP2.

Genevestigator

P08253.

GermOnline

ENSG00000087245. Homo sapiens.

Family and domain databases

Gene3D

1.10.101.10. 1 hit.
2.10.10.10. 3 hits.
2.110.10.10. 1 hit.
3.40.390.10. 2 hits.

InterPro

IPR000562. FN_type2_col-bd.
IPR000585. Hemopexin-like_dom.
IPR018487. Hemopexin-like_repeat.
IPR018486. Hemopexin_CS.
IPR013806. Kringle-like.
IPR024079. MetalloPept_cat_dom.
IPR001818. Pept_M10_metallopeptidase.
IPR021190. Pept_M10A.
IPR021158. Pept_M10A_Zn_BS.
IPR006026. Peptidase_Metallo.
IPR002477. Peptidoglycan-bd-like.
[Graphical view]

Pfam

PF00040. fn2. 3 hits.
PF00045. Hemopexin. 4 hits.
PF00413. Peptidase_M10. 1 hit.
PF01471. PG_binding_1. 1 hit.
[Graphical view]

PRINTS

PR00138. MATRIXIN.

SMART

SM00059. FN2. 3 hits.
SM00120. HX. 4 hits.
SM00235. ZnMc. 1 hit.
[Graphical view]

SUPFAM

SSF50923. Hemopexin. 1 hit.
SSF57440. Kringle-like. 3 hits.
SSF47090. PGBD_like. 1 hit.

PROSITE

PS00546. CYSTEINE_SWITCH. 1 hit.
PS00023. FN2_1. 3 hits.
PS51092. FN2_2. 3 hits.
PS00024. HEMOPEXIN. 1 hit.
PS00142. ZINC_PROTEASE. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P08253.

ChEMBL

CHEMBL333.

ChiTaRS

MMP2. human.

DrugBank

DB00786. Marimastat.
DB00605. Sulindac.

EvolutionaryTrace

P08253.

GenomeRNAi

4313.

NextBio

16973.

PMAP-CutDB

P08253.

SOURCE

Search...

Entry information

Entry name

MMP2_HUMAN

Accession

Primary (citable) accession number: P08253
Secondary accession number(s): B2R6U1 , B4DWH3, E9PE45, Q9UCJ8

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 1, 1988
Last sequence update:	February 1, 1991
Last modified:	May 1, 2013
This is version 170 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.