P39900 (MMP12_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Macrophage metalloelastase
Short name=MME
EC=3.4.24.65

Alternative name(s):
Macrophage elastase
Short name=ME
Short name=hME
Matrix metalloproteinase-12
Short name=MMP-12

Gene names

Name:	MMP12
Synonyms:	HME

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	470 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	May be involved in tissue injury and remodeling. Has significant elastolytic activity. Can accept large and small amino acids at the P1' site, but has a preference for leucine. Aromatic or hydrophobic residues are preferred at the P1 site, with small hydrophobic residues (preferably alanine) occupying P3.
Catalytic activity	Hydrolysis of soluble and insoluble elastin. Specific cleavages are also produced at 14-Ala-|-Leu-15 and 16-Tyr-|-Leu-17 in the B chain of insulin.
Cofactor	Binds 4 calcium ions per subunit. Binds 2 zinc ions per subunit.
Subcellular location	Secreted › extracellular space › extracellular matrix Probable.
Tissue specificity	Found in alveolar macrophages but not in peripheral blood monocytes.
Induction	By exposure to bacterial lipopolysaccharides (LPS). Inhibited by dexamethasone.
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
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 Reference proteome
Gene Ontology (GO)
Biological_process	positive regulation of epithelial cell proliferation involved in wound healing Inferred from direct assay PubMed 15802269. Source: BHF-UCL proteolysis Traceable author statement Ref.1. Source: ProtInc wound healing, spreading of epidermal cells Inferred from direct assay PubMed 15802269. Source: BHF-UCL
Cellular_component	proteinaceous extracellular matrix Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	calcium ion binding Inferred from electronic annotation. Source: InterPro metalloendopeptidase activity Traceable author statement Ref.1. Source: UniProtKB zinc ion binding Traceable author statement Ref.1. Source: ProtInc
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 16

16

Probable

Propeptide

17 – 105

89

Activation peptide By similarity

PRO_0000028776

Chain

106 – 470

365

Macrophage metalloelastase

PRO_0000028777

Regions

Domain

288 – 330

43

Hemopexin-like 1

Domain

332 – 375

44

Hemopexin-like 2

Domain

380 – 427

48

Hemopexin-like 3

Domain

429 – 470

42

Hemopexin-like 4

Motif

90 – 97

8

Cysteine switch By similarity

Sites

Active site

219

1

Metal binding

92

1

Zinc 2; in inhibited form By similarity

Metal binding

124

1

Calcium 1

Metal binding

158

1

Calcium 2

Metal binding

168

1

Zinc 1

Metal binding

170

1

Zinc 1

Metal binding

175

1

Calcium 3

Metal binding

176

1

Calcium 3; via carbonyl oxygen

Metal binding

178

1

Calcium 3; via carbonyl oxygen

Metal binding

180

1

Calcium 3; via carbonyl oxygen

Metal binding

183

1

Zinc 1

Metal binding

190

1

Calcium 2; via carbonyl oxygen

Metal binding

192

1

Calcium 2; via carbonyl oxygen

Metal binding

194

1

Calcium 2

Metal binding

196

1

Zinc 1

Metal binding

198

1

Calcium 3

Metal binding

199

1

Calcium 1

Metal binding

201

1

Calcium 1

Metal binding

201

1

Calcium 3

Metal binding

218

1

Zinc 2; catalytic

Metal binding

222

1

Zinc 2; catalytic

Metal binding

228

1

Zinc 2; catalytic

Metal binding

289

1

Calcium 4; via carbonyl oxygen By similarity

Metal binding

333

1

Calcium 4; via carbonyl oxygen By similarity

Metal binding

381

1

Calcium 4; via carbonyl oxygen By similarity

Metal binding

430

1

Calcium 4; via carbonyl oxygen By similarity

Amino acid modifications

Glycosylation

20

1

N-linked (GlcNAc...) Potential

Glycosylation

285

1

N-linked (GlcNAc...) Potential

Disulfide bond

282 ↔ 470

By similarity

Natural variations

Natural variant

357

1

N → S. Ref.2 Ref.5
Corresponds to variant rs652438 [ dbSNP | Ensembl ].

VAR_021343

Natural variant

469

1

G → R. Ref.2
Corresponds to variant rs28381701 [ dbSNP | Ensembl ].

VAR_021344

Secondary structure

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470

Helix Strand Turn

Details...

Beta strand

106 – 108

3

Beta strand

110 – 118

9

Beta strand

123 – 125

3

Helix

127 – 142

16

Beta strand

144 – 146

3

Beta strand

148 – 151

4

Beta strand

153 – 155

3

Beta strand

158 – 164

7

Beta strand

169 – 171

3

Beta strand

176 – 179

4

Beta strand

182 – 184

3

Beta strand

187 – 189

3

Turn

190 – 193

4

Beta strand

195 – 198

4

Beta strand

203 – 211

9

Helix

212 – 223

12

Turn

232 – 236

5

Beta strand

237 – 239

3

Helix

245 – 247

3

Helix

252 – 259

8

Beta strand

260 – 262

3

Beta strand

266 – 268

3

Beta strand

281 – 284

4

Beta strand

291 – 294

4

Beta strand

297 – 302

6

Beta strand

305 – 308

4

Beta strand

318 – 320

3

Helix

321 – 324

4

Beta strand

334 – 338

5

Helix

339 – 341

3

Beta strand

343 – 348

6

Beta strand

351 – 354

4

Beta strand

357 – 360

4

Turn

361 – 363

3

Beta strand

365 – 367

3

Turn

368 – 372

5

Beta strand

382 – 386

5

Turn

387 – 390

4

Beta strand

391 – 396

6

Beta strand

399 – 404

6

Turn

405 – 408

4

Helix

418 – 421

4

Beta strand

430 – 435

6

Turn

436 – 438

3

Beta strand

439 – 444

6

Beta strand

447 – 452

6

Turn

453 – 456

4

Beta strand

457 – 463

7

Turn

464 – 469

6

Sequences

	Sequence		Length	Mass (Da)
	P39900 [UniParc]. Last modified February 1, 1995. Version 1. Checksum: 8C745EEA8C0EA216	FASTA	470	54,002
	10 20 30 40 50 60 MKFLLILLLQ ATASGALPLN SSTSLEKNNV LFGERYLEKF YGLEINKLPV TKMKYSGNLM 70 80 90 100 110 120 KEKIQEMQHF LGLKVTGQLD TSTLEMMHAP RCGVPDVHHF REMPGGPVWR KHYITYRINN 130 140 150 160 170 180 YTPDMNREDV DYAIRKAFQV WSNVTPLKFS KINTGMADIL VVFARGAHGD FHAFDGKGGI 190 200 210 220 230 240 LAHAFGPGSG IGGDAHFDED EFWTTHSGGT NLFLTAVHEI GHSLGLGHSS DPKAVMFPTY 250 260 270 280 290 300 KYVDINTFRL SADDIRGIQS LYGDPKENQR LPNPDNSEPA LCDPNLSFDA VTTVGNKIFF 310 320 330 340 350 360 FKDRFFWLKV SERPKTSVNL ISSLWPTLPS GIEAAYEIEA RNQVFLFKDD KYWLISNLRP 370 380 390 400 410 420 EPNYPKSIHS FGFPNFVKKI DAAVFNPRFY RTYFFVDNQY WRYDERRQMM DPGYPKLITK 430 440 450 460 470 NFQGIGPKID AVFYSKNKYY YFFQGSNQFE YDFLLQRITK TLKSNSWFGC

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning and characterization of a unique elastolytic metalloproteinase produced by human alveolar macrophages." Shapiro S.D., Kobayashi D.K., Ley T.J. J. Biol. Chem. 268:23824-23829(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Alveolar macrophage.
[2]	NIEHS SNPs program Submitted (DEC-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS SER-357 AND ARG-469.
[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]. Tissue: Esophagus.
[4]	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 (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"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 SER-357.
[6]	"Hydrolysis of a broad spectrum of extracellular matrix proteins by human macrophage elastase." Gronski T.J. Jr., Martin R.L., Kobayashi D.K., Walsh B.C., Holman M.C., Huber M., Van Wart H.E., Shapiro S.D. J. Biol. Chem. 272:12189-12194(1997) [PubMed] [Europe PMC] [Abstract] Cited for: CHARACTERIZATION.
[7]	"Substrate specificity determinants of human macrophage elastase (MMP-12) based on the 1.1 A crystal structure." Lang R., Kocourek A., Braun M., Tschesche H., Huber R., Bode W., Maskos K. J. Mol. Biol. 312:731-742(2001) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.09 ANGSTROMS) OF 106-263.
[8]	"Crystal structure of human macrophage elastase (MMP-12) in complex with a hydroxamic acid inhibitor." Nar H., Werle K., Bauer M.M.T., Dollinger H., Jung B. J. Mol. Biol. 312:743-751(2001) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 100-280.
+	Additional computationally mapped references.

Web resources

NIEHS-SNPs

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

L23808 mRNA. Translation: AAA58658.1. Sequence problems.
AY856072 Genomic DNA. Translation: AAW29944.1.
AK313959 mRNA. Translation: BAG36675.1.
CH471065 Genomic DNA. Translation: EAW67033.1.
BC112301 mRNA. Translation: AAI12302.1.
BC143773 mRNA. Translation: AAI43774.1.

IPI

IPI00298246.

PIR

A49499.

RefSeq

NP_002417.2. NM_002426.4.

UniGene

Hs.1695.
Hs.709832.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1JIZ	X-ray	2.60	A/B	100-264	[»]
1JK3	X-ray	1.09	A	106-263	[»]
1OS2	X-ray	2.15	A/B/C/D/E/F	106-268	[»]
1OS9	X-ray	1.85	A/B/C/D/E/F	106-268	[»]
1RMZ	X-ray	1.34	A	106-263	[»]
1ROS	X-ray	2.00	A/B	106-268	[»]
1UTT	X-ray	2.20	A	106-264	[»]
1UTZ	X-ray	2.50	A/B	106-264	[»]
1Y93	X-ray	1.03	A	106-263	[»]
1YCM	NMR	-	A	106-263	[»]
1Z3J	NMR	-	A	106-263	[»]
2HU6	X-ray	1.32	A	106-263	[»]
2JXY	NMR	-	A	278-470	[»]
2K2G	NMR	-	A	100-263	[»]
2K9C	NMR	-	A	112-263	[»]
2KRJ	NMR	-	A	112-263	[»]
2OXU	X-ray	1.24	A	106-263	[»]
2OXW	X-ray	1.15	A	106-263	[»]
2OXZ	X-ray	1.90	A	106-263	[»]
2POJ	NMR	-	A	100-263	[»]
2W0D	X-ray	2.00	A/B/C/D	106-263	[»]
2WO8	X-ray	2.00	A/B/C/D	106-268	[»]
2WO9	X-ray	1.70	A/B/C/D	106-268	[»]
2WOA	X-ray	2.30	A/B/C/D	106-268	[»]
2Z2D	NMR	-	A	100-263	[»]
3BA0	X-ray	3.00	A	106-470	[»]
3EHX	X-ray	1.90	A	106-263	[»]
3EHY	X-ray	1.90	A	106-263	[»]
3F15	X-ray	1.70	A	106-263	[»]
3F16	X-ray	1.16	A	106-263	[»]
3F17	X-ray	1.10	A	106-263	[»]
3F18	X-ray	1.13	A	106-263	[»]
3F19	X-ray	1.13	A	106-263	[»]
3F1A	X-ray	1.25	A	106-263	[»]
3LIK	X-ray	1.80	A	106-263	[»]
3LIL	X-ray	1.80	A	106-263	[»]
3LIR	X-ray	1.90	A	106-263	[»]
3LJG	X-ray	1.31	A	106-263	[»]
3LK8	X-ray	1.80	A	106-263	[»]
3LKA	X-ray	1.80	A	106-263	[»]
3N2U	X-ray	1.81	A	106-263	[»]
3N2V	X-ray	1.55	A	106-263	[»]
3NX7	X-ray	1.80	A	106-263	[»]
3RTS	X-ray	1.81	A	106-263	[»]
3RTT	X-ray	1.82	A	106-263	[»]
3TS4	X-ray	1.59	A	106-263	[»]
3TSK	X-ray	2.00	A	106-263	[»]
3UVC	X-ray	1.30	A/B	106-263	[»]
4EFS	X-ray	1.63	A	106-263	[»]
4GQL	X-ray	1.15	A	106-263	[»]
4GR0	X-ray	1.50	A	106-263	[»]
4GR3	X-ray	1.49	A	106-263	[»]
4GR8	X-ray	1.30	A	111-262	[»]
4GUY	X-ray	2.00	A	106-263	[»]

ProteinModelPortal

P39900.

ModBase

Search...

Protein-protein interaction databases

STRING

9606.ENSP00000320664.

Protein family/group databases

MEROPS

M10.009.

PTM databases

PhosphoSite

P39900.

Polymorphism databases

DMDM

729179.

Proteomic databases

PaxDb

P39900.

PRIDE

P39900.

Protocols and materials databases

DNASU

4321.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000571244; ENSP00000458585; ENSG00000262406.

GeneID

4321.

KEGG

hsa:4321.

UCSC

uc001phk.3. human.

Organism-specific databases

CTD

4321.

GeneCards

GC11M102767.

HGNC

HGNC:7158. MMP12.

MIM

601046. gene.

neXtProt

NX_P39900.

PharmGKB

PA30870.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG323958.

HOGENOM

HOG000217927.

HOVERGEN

HBG052484.

InParanoid

P39900.

KO

K01413.

OrthoDB

EOG4TXBRN.

Enzyme and pathway databases

Reactome

REACT_118779. Extracellular matrix organization.

Gene expression databases

CleanEx

HS_MMP12.

Genevestigator

P39900.

GermOnline

ENSG00000110347. 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

P39900.

ChEMBL

CHEMBL4393.

ChiTaRS

MMP12. human.

DrugBank

DB00551. Acetohydroxamic Acid.

EvolutionaryTrace

P39900.

GenomeRNAi

4321.

NextBio

17001.

SOURCE

Search...

Entry information

Entry name

MMP12_HUMAN

Accession

Primary (citable) accession number: P39900
Secondary accession number(s): B2R9X8, B7ZLF6, Q2M1L9

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1995
Last sequence update:	February 1, 1995
Last modified:	May 1, 2013
This is version 145 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.