Matrix metalloproteinase

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Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs belong to a larger family of proteases known as the metzincin superfamily.

Collectively they are capable of degrading all kinds of extracellular matrix proteins, but also can process a number of bioactive molecules. They are known to be involved in the cleavage of cell surface receptors, the release of apoptotic ligands (such as the FAS ligand), and chemokine in/activation. MMPs are also thought to play a major role on cell behaviors such as cell proliferation, migration (adhesion/dispersion), differentiation, angiogenesis, apoptosis and host defense.

They were first described in vertebrates (1962), including Homo sapiens, but have since been found in invertebrates and plants. They are distinguished from other endopeptidases by their dependence on metal ions as cofactors, their ability to degrade extracellular matrix, and their specific evolutionary DNA sequence.

Contents 1 History 2 Structure 2.1 The pro-peptide 2.2 The catalytic domain 2.3 The hinge region 2.4 The haemopexin-like C-terminal domain 2.5 Catalytic mechanism 3 Classification 3.1 Evolutionary 3.2 Functional 3.3 Genes 4 Function 5 Activation 6 Inhibitors 7 Pharmacology 8 References 9 External links

[edit] History

Initially, MMPs were described by Jerome Gross and Charles Lapiere (1962) who observed enzymatic activity (collagen triple helix degradation) during tadpole tail metamorphosis.^[2] Therefore, the enzyme was named interstitial collagenase (MMP-1).

Later it was purified from human skin (1968)^[3], and was recognized to be synthesized as a zymogen.^[4]

The "cysteine switch" was described in 1990.^[5]

[edit] Structure

The MMPs share a common domain structure. The three common domains are the pro-peptide, the catalytic domain and the haemopexin-like C-terminal domain which is linked to the catalytic domain by a flexible hinge region.

[edit] The pro-peptide

The MMPs are initially synthesized as inactive zymogens with a pro-peptide domain that must be removed before the enzyme is active. The pro-peptide domain is part of the “cysteine switch.” This contains a conserved cysteine residue which interacts with the zinc in the active site and prevents binding and cleavage of the substrate keeping the enzyme in an inactive form. In the majority of the MMPs, the cysteine residue is in the conserved sequence PRCGxPD. Some MMPs have a prohormone convertase cleavage site (Furin-like) as part of this domain which, when cleaved, activates the enzyme. MMP-23A and MMP-23B include a transmembrane segment in this domain.^[6]

[edit] The catalytic domain

X-ray crystallographic structures of several MMP catalytic domains have shown that this domain is an oblate sphere measuring 35 x 30 x 30 Å (3.5 x 3 x 3 nm). The active site is a 20 Å (2 nm) groove that runs across the catalytic domain. In the part of the catalytic domain forming the active site there is a catalytically important Zn²⁺ ion, which is bound by three histidine residues found in the conserved sequence HExxHxxGxxH. Hence, this sequence is a zinc-binding motif.

The gelatinases, such as MMP-2, incorporate Fibronectin type II modules inserted immediately before in the zinc-binding motif in the catalytic domain.^[7]

[edit] The hinge region

The catalytic domain is connected to the C-terminal domain by a flexible hinge or linker region. This is up to 75 amino acids long, and has no determinable structure.

[edit] The haemopexin-like C-terminal domain

The C-terminal domain has structural similarities to the serum protein haemopexin. It has a four bladed β-propeller structure. β-propeller structures provide a large flat surface which is thought to be involved in protein-protein interactions. This determines substrate specificity and is the site for interaction with TIMP’s (tissue inhibitor of metalloproteinases). The haemopexin-like domain is absent in MMP-7, MMP-23, MMP-26 and the plant and nematode. MT-MMPs are anchored to the plasma membrane, through this domain and some of these have cytoplasmic domains.

[edit] Catalytic mechanism

There are three catalytic mechanisms published.

• In the first mechanism, Browner M.F. and colleagues^[8]proposed the base-catalysis mechanism, carried out by the conserved glutamate residue and the Zn²⁺ ion.

• In the second mechanism, the Matthews-mechanism, Kester and Matthews^[9] suggested an interaction between a water molecule and the Zn²⁺ ion during the acid-base catalysis.

• In the third mechanism, the Manzetti-mechanism, Manzetti Sergio and colleagues^[10] provided evidence that a coordination between water and zinc during catalysis was unlikely, and suggested a third mechanism wherein a histidine from the HExxHxxGxxH-motif participates in catalysis by allowing the Zn²⁺ ion to assume a quasi-penta coordinated state, via its dissociation from it. In this state, the Zn²⁺ ion is coordinated with the two oxygen atoms from the catalytic glutamic acid, the substrate's carbonyl oxygen atom, and the two histidine residues, and can polarize the glutamic acid's oxygen atom, proximate the scissile bond, and induce it to act as reversible electron donor. This forms an oxyanion transition state. At this stage, a water molecule acts on the dissociated scissile bond and completes the hydrolyzation of the the substrate.

[edit] Classification

The MMPs can be subdivided in different ways.

[edit] Evolutionary

Use of bioinformatic methods to compare the primary sequences of the MMPs suggest the following evolutionary groupings of the MMPs:

• MMP-19
• MMPs 11, 14, 15, 16 and 17
• MMP-2 and MMP-9
• all the other MMPs

Analysis of the catalytic domains in isolation suggests that the catalytic domains evolved further once the major groups had differentiated, as is also indicated by the substrate specificities of the enzymes.

[edit] Functional

The most commonly used groupings (by researchers in MMP biology) are based partly on historical assessment of the substrate specificity of the MMP and partly on the cellular localisation of the MMP. These groups are the collagenases, the gelatinases, the stromelysins, and the membrane type MMPs (MT-MMPs).

• The collagenases are capable of degrading triple-helical fibrillar collagens into distinctive 3/4 and 1/4 fragments. These collagens are the major components of bone and cartilage, and MMPs are the only known mammalian enzymes capable of degrading them. Traditionally, the collagenases are #1, #8, #13, and #18. In addition, #14 has also been shown to cleave fibrillar collagen, and more controversially there is evidence that #2 is capable of collagenolysis. In MeSH, the current list of collegenases includes #1, #2, #8, #9, and #13. #14 is present in MeSH but not listed as a collegenase, while #18 is absent from MeSH.

• The main substrates of the gelatinases are type IV collagen and gelatin, and these enzymes are distinguished by the presence of an additional domain inserted into the catalytic domain. This gelatin-binding region is positioned immediately before the zinc binding motif, and forms a separate folding unit which does not disrupt the structure of the catalytic domain. The gelatinases are #2 and #9.

• The stromelysins display a broad ability to cleave extracellular matrix proteins but are unable to cleave the triple-helical fibrillar collagens. The three canonical members of this group are #3, #10, and #11.

• All six membrane type MMPs (#14, #15, #16, #17, #24, and #25) have a furin cleavage site in the pro-peptide, which is a feature also shared by #11.

However, it is becoming increasingly clear that these divisions are somewhat artificial as there are a number of MMPs that do not fit into any of the traditional groups.

[edit] Genes

Gene	Name	Location	Description
MMP1	Interstitial collagenase	secreted
MMP2	Gelatinase-A, 72 kDa gelatinase	secreted
MMP3	Stromelysin 1	secreted
MMP7	Matrilysin, PUMP 1	secreted
MMP8	Neutrophil collagenase	secreted
MMP9	Gelatinase-B, 92 kDa gelatinase	secreted
MMP10	Stromelysin 2	secreted
MMP11	Stromelysin 3	secreted	MMP-11 shows more similarity to the MT-MMPs, is convertase-activatable and is secreted therefore usually associated to convertase-activatable MMPs.
MMP12	Macrophage metalloelastase	secreted
MMP13	Collagenase 3	secreted
MMP14	MT1-MMP	membrane-associated	type-I transmembrane MMP
MMP15	MT2-MMP	membrane-associated	type-I transmembrane MMP
MMP16	MT3-MMP	membrane-associated	type-I transmembrane MMP
MMP17	MT4-MMP	membrane-associated	glycosyl phosphatidylinositol-attached
MMP18	Collagenase 4, xcol4, xenopus collagenase	-	No known human orthologue
MMP19	RASI-1, occasionally referred to as stromelysin-4	-
MMP20	Enamelysin	secreted
MMP21	X-MMP	secreted
MMP23A	CA-MMP	membrane-associated	type-II transmembrane cysteine array
MMP23B	-	membrane-associated	type-II transmembrane cysteine array
MMP24	MT5-MMP	membrane-associated	type-I transmembrane MMP
MMP25	MT6-MMP	membrane-associated	glycosyl phosphatidylinositol-attached
MMP26	Matrilysin-2, endometase	-
MMP27	MMP-22, C-MMP	-
MMP28	Epilysin	secreted	Was discovered in 2001 and given its name due to have been discovered in human keratinocytes. Highly expressed in lung, placenta, salivary glands, heart, uterus, skin. Contains a threonine in place of proline in its cysteine switch (PRCGVTD).

[edit] Function

The MMPs play an important role in tissue remodeling associated with various physiological and pathological processes such as morphogenesis, angiogenesis, tissue repair, cirrhosis, arthritis and metastasis. MMP-2 and MMP-9 are thought to be important in metastasis. MMP-1 is thought to be important in rheumatoid and osteo-arthritis.

[edit] Activation

All MMPs are synthesized in the latent form ( Zymogen ). They are secreted as proenzymes and require extracellular activation. They can be activated in vitro by many mechanisms including organomercurials, chaotropic agents and other proteases .

[edit] Inhibitors

The MMPs are inhibited by specific endogenous tissue inhibitor of metalloproteinases (TIMPs), which comprise a family of four protease inhibitors: TIMP-1, TIMP-2, TIMP-3 and TIMP-4.

Synthetic inhibitors generally contain a chelating group which binds the catalytic zinc atom at the MMP active site tightly. Common chelating groups include hydroxamates, carboxylates, thiols, and phosphinyls. Hydroxymates are particularly potent inhibitors of MMPs and other zinc-dependent enzymes, due to their bidentate chelation of the zinc atom. Other substitutents of these inhibitors are usually designed to interact with various binding pockets on the MMP of interest, making the inhibitor more or less specific for given MMPs.

[edit] Pharmacology

Doxycycline, at subantimicrobial doses, inhibits MMP activity, and has been used in various experimental systems for this purpose. It is used clinically for the treatment of periodontal disease and is the only MMP inhibitor which is widely available clinically. It is sold under the trade name Periostat by the company CollaGenex. Minocycline, another tetracycline antibiotic, has also been shown to inhibit MMP activity.

A number of rationally designed MMP inhibitors have shown some promise in the treatment of pathologies which MMPs are suspected to be involved in (see above). However, most of these, such as marimastat (BB-2516), a broad spectrum MMP inhibitor, and trocade (Ro 32-3555), an MMP-1 selective inhibitor, have performed poorly in clinical trials. The failure of Marimastat was partially responsible for the folding of British Biotech, which developed it. The failure of these drugs has been largely due to toxicity (particularly musculo-skeletal toxicity in the case of broad spectrum inhibitors) and failure to show expected results (in the case of trocade, promising results in rabbit arthritis models were not replicated in human trials). The reasons behind the largely disappointing clinical results of MMP inhibitors is unclear, especially in light of their activity in animal models.

[edit] References

[edit] External links

• The Matrix Metalloproteinase Protein
• Extracellular proteolysis at fibrinolysis.org
• Currently identified substrates for mammalian MMPs at clip.ubc.ca
• MeSH Matrix+metalloproteinases

v • d • e Proteases: metalloendopeptidases (EC 3.4.24) ADAM proteins Alpha secretases (ADAM9 · ADAM10 · ADAM17 · ADAM19) · ADAM2 · ADAM7 · ADAM8 · ADAM11 · ADAM12 · ADAM15 · ADAM18 · ADAM22 · ADAM23 · ADAM28 · ADAM33 · ADAMTS1 · ADAMTS2 · ADAMTS3 · ADAMTS4 · ADAMTS5 · ADAMTS8 · ADAMTS9 · ADAMTS10 · ADAMTS12 · ADAMTS13 Matrix metalloproteinase Collagenase · Gelatinase Other Neprilysin · Procollagen peptidase · Thermolysin · Pregnancy-associated plasma protein A · Bone morphogenetic protein 1 · Insulysin · Lysostaphin · Insulin degrading enzyme