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.
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[edit] History
Initially, MMPs were described by Jermome Gross and Charles Lapiere (1962) who observed enzymatic activity (collagen triple helix degradation) during tadpole tail metamorphosis (PMID 13902219). Therefore, the enzyme was named interstitial collagenase (MMP-1). Later it was purified from human skin (1968) (PMID 4967132), and was recognized to be synthezised as a zymogen (PMID 4331330). The description of the "cysteine switch" was described in 1990 (PMID 2164689).
[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 synthesised as inactive zymogens with a pro-peptide domain that must be removed before the enzyme is active. The pro-peptide domain is part of “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 (PMID 10945999).
[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 (PMID 12486137).
[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. 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] Classification
[edit] Placing the MMPs in the peptidase families
The MMP family of endopeptidases is part of a larger group of proteases called the metzincins. These enzymes have a common zinc binding motif (HExxHxxGxxH) in their active site, and a conserved methionine turn following the active site. Other members of the metzincins are the serralysins, the astacins, and the adamalysins.
[edit] Subdivisions of the MMPs
The MMPs can be subdivided in different ways. 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. 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). 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] Archetypal MMPs
[edit] The collagenases
These MMPs 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:
- MMP-1 (Interstitial collagenase)
- MMP-8 (Neutrophil collagenase)
- MMP-13 (Collagenase 3)
- MMP-18 (Collagenase 4, xcol4, xenopus collagenase. No known human orthologue)
MMP-14 (MT1-MMP) has also been shown to cleave fibrillar collagen, and more controversially there is evidence that MMP-2 is capable of collagenolysis.
[edit] The stromelysins
These enzymes 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:
- MMP-3 (Stromelysin 1)
- MMP-10 (Stromelysin 2)
- MMP-11 (Stromelysin 3)
MMP-11 shows more similarity to the MT-MMPs, is convertase-activatable and is secreted therefore usually associated to convertase-activatable MMPs.
[edit] Other MMPs
- MMP-12 (Macrophage metalloelastase)
- MMP-19 (RASI-1, occasionally referred to as stromelysin-4)
- Enamelysin (MMP-20)
- MMP-27 (MMP-22, C-MMP)
[edit] The matrilysins
- MMP-7 (Matrilysin, PUMP)
- MMP-26 (Matrilysin-2, endometase)
[edit] The gelatinases
The main substrates of these MMPs 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 two members of this sub-group are:
- MMP-2 (72 kDa gelatinase, gelatinase-A)
- MMP-9 (92 kDa gelatinase, gelatinase-B).
[edit] Convertase-activatable MMPs
[edit] Secreted
- MMP-11 (Stromelysin 3)
- MMP-21 (X-MMP)
- MMP-28 (Epilysin) - 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] The membrane-bound MMPs
The membrane-bound MMPs include:
- The type-II transmembrane cysteine array MMP-23,
- The glycosyl phosphatidylinositol-attached MMPs 17 and 25 (MT4-MMP and MT6-MMP respectively), and
- The type-I transmembrane MMPs 14, 15, 16, 24 (MT1-MMP, MT2-MMP, MT3-MMP, and MT5-MMP respectively).
All 6 MT-MMPs have a furin cleavage site in the pro-peptide, which is a feature also shared by MMP-11.
[edit] Other
- MMP-23A (CA-MMP)
- MMP-23B
[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] 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. Overall, all MMPs are inhibited by TIMPs once they are activated but the gelatinases (MMP-2 and MMP-9) can form complexes with TIMPs when the enzymes are in the latent form. The complex of latent MMP-2 (pro-MMP-2)with TIMP-2 serves to facilitate the activation of pro-MMP-2 at the cell surface by MT1-MMP (MMP-14), a membrane-anchored MMP. The role of the pro-MMP-9/TIMP-1 complex is still unknown.
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.
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.
