MMP3

Matrix metallopeptidase 3 (stromelysin 1, progelatinase)
PDB rendering based on 1b3d.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1B3D, 1B8Y, 1BIW, 1BM6, 1BQO, 1C3I, 1C8T, 1CAQ, 1CIZ, 1CQR, 1D5J, 1D7X, 1D8F, 1D8M, 1G05, 1G49, 1G4K, 1HFS, 1HY7, 1M1W, 1OO9, 1QIA, 1QIC, 1SLM, 1SLN, 1UEA, 1UMS, 1UMT, 1USN, 2D1O, 2JNP, 2JT5, 2JT6, 2SRT, 2USN, 3OHL, 3OHO, 3USN, 4DPE, 4G9L, 4JA1
Identifiers
Symbols	MMP3 ; CHDS6; MMP-3; SL-1; STMY; STMY1; STR1
External IDs	OMIM: 185250 MGI: 97010 HomoloGene: 20545 IUPHAR: 1630 ChEMBL: 283 GeneCards: MMP3 Gene
EC number	3.4.24.17
Gene ontology Molecular function • endopeptidase activity • metalloendopeptidase activity • calcium ion binding • zinc ion binding Cellular component • extracellular region • proteinaceous extracellular matrix • extracellular space Biological process • proteolysis • negative regulation of hydrogen peroxide metabolic process • extracellular matrix disassembly • extracellular matrix organization • regulation of cell migration • collagen catabolic process • cellular response to amino acid stimulus Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	4314	17392
Ensembl	ENSG00000149968	ENSMUSG00000043613
UniProt	P08254	P28862
RefSeq (mRNA)	NM_002422	NM_010809
RefSeq (protein)	NP_002413	NP_034939
Location (UCSC)	Chr 11: 102.71 – 102.71 Mb	Chr 9: 7.45 – 7.46 Mb
PubMed search

Stromelysin-1 also known as matrix metalloproteinase-3 (MMP-3) is an enzyme that in humans is encoded by the MMP3 gene. The MMP3 gene is part of a cluster of MMP genes which localize to chromosome 11q22.3.^[1] MMP-3 has an estimated molecular weight of 54 kDa.^[2]

Function

Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix and during tissue remodeling in normal physiological processes, such as embryonic development and reproduction, as well as in disease processes, such as arthritis, and tumour metastasis. Most MMPs are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. The MMP-3 enzyme degrades collagen types II, III, IV, IX, and X, proteoglycans, fibronectin, laminin, and elastin. In addition, MMP-3 can also activate other MMPs such as MMP-1, MMP-7, and MMP-9, rendering MMP-3 crucial in connective tissue remodeling.^[3] The enzyme is thought to be involved in wound repair, progression of atherosclerosis, and tumor initiation. Nuclear MMP3 functions as a transcription factor and a proteinase.^[4]

Gene regulation

Expression of MMP3 is primarily regulated at the level of transcription, where the promoter of the gene responds to various stimuli, including growth factors, cytokines, tumor promoters, and oncogene products.^[5] A polymorphism in the promoter of the MMP3 gene was first reported in 1995.^[6] The polymorphism is due to variation in the number of adenosines located at position -1171 relative to the transcription start site, resulting in one allele having five adenosines (5A) and the other allele having six adenosines (6A). In vitro promoter functional analyses showed that the 5A allele had greater promoter activities as compared with the 6A allele.^[3] It has been shown in different studies that individuals carrying the 5A allele have increased susceptibility to diseases attributed to increased MMP expression, such as acute myocardial infarction and abdominal aortic aneurysm.^[7][8] On the other hand, the 6A allele has been found to be associated with diseases characterized by insufficient MMP-3 expression due to a lower promoter activity of the 6A allele, such as progressive coronary atherosclerosis.^[3][9][10] The -1171 5A/6A variant has also been associated with congenital anomalies such as cleft lip and palate, where individuals with cleft lip/palate presented significantly more 6A/6A genotypes than controls.^[11] MMP3 as a transcription factor regulates CTGF/CCN2 gene. ^[4]

Recently, the MMP3 gene was shown to be down-regulated in individuals with cleft lip and palate when compared to controls,^[12] reinforcing the nature of cleft lip/palate as a condition resulting from insufficient or defective embryonic tissue remodeling.

Structure

Most members of the MMP family are organized into three basic, distinctive, and well-conserved domains based on structural considerations: an amino-terminal propeptide; a catalytic domain; and a hemopexin-like domain at the carboxy-terminal. The propeptide consists of approximately 80–90 amino acids containing a cysteine residue, which interacts with the catalytic zinc atom via its side chain thiol group. A highly conserved sequence (. . .PRCGXPD. . .) is present in the propeptide. Removal of the propeptide by proteolysis results in zymogen activation, as all members of the MMP family are produced in a latent form. The catalytic domain contains two zinc ions and at least one calcium ion coordinated to various residues. One of the two zinc ions is present in the active site and is involved in the catalytic processes of the MMPs. The second zinc ion (also known as structural zinc) and the calcium ion are present in the catalytic domain approximately 12 Å away from the catalytic zinc. The catalytic zinc ion is essential for the proteolytic activity of MMPs; the three histidine residues that coordinate with the catalytic zinc are conserved among all the MMPs. Little is known about the roles of the second zinc ion and the calcium ion within the catalytic domain, but the MMPs are shown to possess high affinities for structural zinc and calcium ions. The hemopexin-like domain of MMPs is highly conserved and shows sequence similarity to the plasma protein, hemopexin. The hemopexin-like domain has been shown to play a functional role in substrate binding and/or in interactions with the tissue inhibitors of metalloproteinases (TIMPs), a family of specific MMP protein inhibitors. In addition to these basic domains, the family of MMPs evolved into different subgroups by incorporating and/or deleting structural and functional domains. For example, MMP-2 and MMP-9, also known as gelatinases, incorporated the three repeats homologous to the type-II module of fibronectin into the catalytic domain that has been shown to be involved in binding to denatured collagen or gelatin. This domain, known as the gelatin binding domain or fibronectin type-II-like domain, is unique to the gelatinases, and so these enzymes are regarded as a separate subgroup among members of the MMP family. Incorporation of a hydrophobic stretch of approximately 25 amino acids, representing a putative transmembrane domain at the carboxy terminus and recognition motif (RXKR) for furin-like convertases at the end of the propeptide domain, is a characteristic of the membrane-type MMPs (MT-MMPs) except MT4-MMP (vide infra). MMP-11 also contains this furin recognition motif and, similar to the MT-MMPs, it is processed into the active form intracellularly. Additional insertion to the three basic MMP domains also includes a proline-rich 54 amino acid insertion in MMP-9 with sequence similarity to the α2 chain of collagen V. Finally, MMP-7 lacks the hemopexin-like domain and represents the smallest member of the MMP family.^[13]

References

Further reading

External links

• The MEROPS online database for peptidases and their inhibitors: M10.005

PDB gallery 1b3d: STROMELYSIN-1  1b8y: X-RAY STRUCTURE OF HUMAN STROMELYSIN CATALYTIC DOMAIN COMPLEXED WITH NON-PEPTIDE INHIBITORS: IMPLICATIONS FOR INHIBITOR SELECTIVITY  1biw: DESIGN AND SYNTHESIS OF CONFORMATIONALLY-CONSTRAINED MMP INHIBITORS  1bm6: SOLUTION STRUCTURE OF THE CATALYTIC DOMAIN OF HUMAN STROMELYSIN-1 COMPLEXED TO A POTENT NON-PEPTIDIC INHIBITOR, NMR, 20 STRUCTURES  1bqo: DISCOVERY OF POTENT, ACHIRAL MATRIX METALLOPROTEINASE INHIBITORS  1c3i: HUMAN STROMELYSIN-1 CATALYTIC DOMAIN COMPLEXED WITH RO-26-2812  1c8t: HUMAN STROMELYSIN-1 (E202Q) CATALYTIC DOMAIN COMPLEXED WITH RO-26-2812  1caq: X-RAY STRUCTURE OF HUMAN STROMELYSIN CATALYTIC DOMAIN COMPLEXES WITH NON-PEPTIDE INHIBITORS: IMPLICATION FOR INHIBITOR SELECTIVITY  1ciz: X-RAY STRUCTURE OF HUMAN STROMELYSIN CATALYTIC DOMAIN COMPLEXES WITH NON-PEPTIDE INHIBITORS: IMPLICATION FOR INHIBITOR SELECTIVITY  1cqr: CRYSTAL STRUCTURE OF THE STROMELYSIN CATALYTIC DOMAIN AT 2.0 A RESOLUTION  1d5j: CRYSTAL STRUCTURE OF MMP3 COMPLEXED WITH A THIAZEPINE BASED INHIBITOR.  1d7x: CRYSTAL STRUCTURE OF MMP3 COMPLEXED WITH A MODIFIED PROLINE SCAFFOLD BASED INHIBITOR.  1d8f: CRYSTAL STRUCTURE OF MMP3 COMPLEXED WITH A PIPERAZINE BASED INHIBITOR.  1d8m: CRYSTAL STRUCTURE OF MMP3 COMPLEXED WITH A HETEROCYCLE-BASED INHIBITOR  1g05: HETEROCYCLE-BASED MMP INHIBITOR WITH P2'SUBSTITUENTS  1g49: A CARBOXYLIC ACID BASED INHIBITOR IN COMPLEX WITH MMP3  1g4k: X-ray Structure of a Novel Matrix Metalloproteinase Inhibitor Complexed to Stromelysin  1hfs: CRYSTAL STRUCTURE OF THE CATALYTIC DOMAIN OF HUMAN FIBROBLAST STROMELYSIN-1 INHIBITED WITH THE N-CARBOXY-ALKYL INHIBITOR L-764,004  1hy7: A CARBOXYLIC ACID BASED INHIBITOR IN COMPLEX WITH MMP3  1oo9: Orientation in Solution of MMP-3 Catalytic Domain and N-TIMP-1 from Residual Dipolar Couplings  1qia: CRYSTAL STRUCTURE OF STROMELYSIN CATALYTIC DOMAIN  1qic: CRYSTAL STRUCTURE OF STROMELYSIN CATALYTIC DOMAIN  1slm: CRYSTAL STRUCTURE OF FIBROBLAST STROMELYSIN-1: THE C-TRUNCATED HUMAN PROENZYME  1sln: CRYSTAL STRUCTURE OF THE CATALYTIC DOMAIN OF HUMAN FIBROBLAST STROMELYSIN-1 INHIBITED WITH THE N-CARBOXY-ALKYL INHIBITOR L-702,842  1uea: MMP-3/TIMP-1 COMPLEX  1ums: STROMELYSIN-1 CATALYTIC DOMAIN WITH HYDROPHOBIC INHIBITOR BOUND, PH 7.0, 32OC, 20 MM CACL2, 15% ACETONITRILE; NMR ENSEMBLE OF 20 STRUCTURES  1umt: STROMELYSIN-1 CATALYTIC DOMAIN WITH HYDROPHOBIC INHIBITOR BOUND, PH 7.0, 32OC, 20 MM CACL2, 15% ACETONITRILE; NMR AVERAGE OF 20 STRUCTURES MINIMIZED WITH RESTRAINTS  1usn: CRYSTAL STRUCTURE OF THE CATALYTIC DOMAIN OF HUMAN FIBROBLAST STROMELYSIN-1 INHIBITED WITH THIADIAZOLE INHIBITOR PNU-142372  2d1o: Stromelysin-1 (MMP-3) complexed to a hydroxamic acid inhibitor  2srt: CATALYTIC DOMAIN OF HUMAN STROMELYSIN-1 AT PH 5.5 AND 40OC COMPLEXED WITH INHIBITOR  2usn: CRYSTAL STRUCTURE OF THE CATALYTIC DOMAIN OF HUMAN FIBROBLAST STROMELYSIN-1 INHIBITED WITH THIADIAZOLE INHIBITOR PNU-141803  3usn: STRUCTURE OF THE CATALYTIC DOMAIN OF HUMAN FIBROBLAST STROMELYSIN-1 INHIBITED WITH THE THIADIAZOLE INHIBITOR IPNU-107859, NMR, 1 STRUCTURE