Review
Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

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Abstract

Human matrix metalloproteinases (MMPs) belong to the M10 family of the MA clan of endopeptidases. They are ubiquitarian enzymes, structurally characterized by an active site where a Zn2+ atom, coordinated by three histidines, plays the catalytic role, assisted by a glutamic acid as a general base. Various MMPs display different domain composition, which is very important for macromolecular substrates recognition. Substrate specificity is very different among MMPs, being often associated to their cellular compartmentalization and/or cellular type where they are expressed. An extensive review of the different MMPs structural and functional features is integrated with their pathological role in several types of diseases, spanning from cancer to cardiovascular diseases and to neurodegeneration. It emerges a very complex and crucial role played by these enzymes in many physiological and pathological processes.

Introduction

The term metallo-proteases encompasses esopeptidase and endopeptidase involved in many biological processes, such as morphogenesis, metabolism of biologically active peptides and hormones, development, regulation of cell cycle, cell proliferation, migration, adhesion and antibiotics metabolism (Nagase, 2001). In the MEROPS database, metallo-protease families are grouped into 14 different clans, namely MA, MC, MD, ME, MJ, MK, MM, MO, MP (these requiring only one catalytic metal ion) and MF, MG, MH, MQ (these containing two metal ions acting co-catalytically). The divalent metal ion contained in the active site is in the vast majority of cases a zinc ion, but cobalt, manganese or nickel are also represented. In humans, the majority of metalloproteinases are zinc metallo-endopeptidases distributed in: clan MA (i.e., M3, M10, M12, M13, M41, M43 and M48 families), clan ME (i.e., M16 family), clan MJ (i.e., M19 and M38 families), clan MK (i.e., M22 family), clan MM (i.e., M50 family). Further, there are three families, namely M49, M76 and M79, which have not been assigned yet to a specific clan. Human metallo-peptidases play important roles in a variety of biological processes and the unbalance of their activity and expression is often at the basis of diseases like cancer, neurodegeneration, inflammation, arthritis, cardiovascular diseases. For this reason, they have been historically represented an intriguing drug targets, even though their therapeutical inhibition have raised many questions, since (i) the activity of these enzymes is pleiotropic so that their inhibition could negatively modulate some cellular functions; (ii) a large number of inhibitors are not selective for a single enzyme (Nagase, 2001). For a detailed properties of a single enzyme, it is possible to refer to the “Handbook of Proteolytic enzymes” (Barret et al., 2004).

This chapter will focus on human matrix metalloproteases, grouped as M10 family. In particular, in the first part this review briefly summarizes other families of MA clan, while in the second part attention will be concentrated on the present knowledge of members of M10 family, with a major focus on their biological functions and involvement in human diseases.

Clan MA is the main clan of metalloproteinases and it is characterized by the “HEXXH” zinc-binding motif with two histidines acting as ligands of the catalytic Zn2+ and the glutamate as the general basis. Proto-typical proteases with this motif are: neurolysin (M3), matrix metalloproteinases (MMP, subfamily A of family M10). Here, we furnish a brief overview of this human family, discussing only representative examples of their functions.

Human proteins included in M3 family are the soluble metallopeptidases neurolysin and thimet oligopeptidase (TOP), which reveal similar biological and biochemical features, and mitochondrial-processing-peptidase (MIP) (Table 1) (see for review Shrimpton et al., 2002, Ferro et al., 2004). Although neurolysin and TOP are well characterized biochemically, their physiopathological role has yet to be established. Both peptidases seem to play important roles in reproduction, nociception and cardiovascular homeostasis (Ferro et al., 2004). In particular, several studies indicate an involvement of neurolysin and TOP in neurotensin degradation (by exerting a broad range of endocrine and cardiovascular effect, such as hypotension, analgesia and hypothermia) and in bradykinin degradation, postulating a direct involvement in blood pressure regulation (Chabry et al., 1990, Checler et al., 1995, Davis et al., 1992, Genden and Molineaux, 1991, Kadonosono et al., 2007, Norman et al., 2003). Additionally TOP inactivates opioids and the gonadotrophin-releasing hormone, suggesting a putative role in the modulation of nociception and reproductive physiology (Cyr et al., 2010, Kest et al., 1991, Shrimpton et al., 2002).

Human members of M12 family are classified in two subfamilies, A and B, which include astacins, ADAM and ADAMTS proteases, respectively (see for review Edwards et al., 2008, Klein and Bischoff, 2011, Mochizuki and Okada, 2007, Murphy, 2008, Tousseyn et al., 2006, Van Goor et al., 2009).

ADAM (a disintegrin and metalloprotease) proteases are type 1 transmembrane proteins, defined by a modular structure encompassing (i) a prodomain, whose removal in the trans-Golgi network by pro-protein convertases is a key step in protease activation (with the exception of ADAM8 and ADAM28, which are activated by an autocatalytic cleavage), (ii) a Zn-binding domain, (iii) a disintegrin domain implicated in ADAMs–integrin interaction, (iv) a cysteine-rich domain which can interact with ECM proteins like fibronectin (as in the case of ADAM13) and also binds to syndecan cell surface proteoglycans (as for ADAM12), (v) a epidermal growth factor (EGF)-like domain, (vi) a transmembrane and (vii) a cytoplasmatic tail that acts as binding site for SH3-domain containing proteins (Gaultier et al., 2002, Howard et al., 2000, Lum et al., 1998, Schlomann et al., 2002, Seals and Courtneidge, 2003, Thodeti et al., 2003, White, 2003, White et al., 2005). Only half of known ADAMs are enzymatically active, since some of them lack one or more critical catalytic residues (Van Goor et al., 2009). ADAM biological functions have been generally linked to fertility, cell adhesion and fusion, cell fate determination in nervous system, aspects of immunity (Edwards et al., 2008). Several data support the roles of at least three ADAMs in the fertilization process; in particular, ADAM2 (fertilin β) and ADAM3 (cyritestin) knockout mice show reduced spermatozoon binding to oolemma and also poor adherence to the zona pellucida, while ADAM1-deficient mice show reduced egg migration from uterus to the oviduct (Cho et al., 1998, Nishimura et al., 2001, Nishimura et al., 2004). ADAM1 and ADAM3 are apparently non functional in humans, since their absence does not impair fertility because it is presumably compensated by other enzymes, such ADAM21 and ADAM30 (Grzmil et al., 2001, Jury et al., 1997). One of the major ADAM functions is the ectodomain shedding of a broad spectrum of transmembrane proteins substrates, including epidermal growth factor (EGFR) ligands, tumor necrosis factor α (TNF-α), cell adhesion molecules like CD44 and cadherins (Blobel, 2005, Nagano et al., 2004, Reiss et al., 2005). Although several ADAMs have sheddase function, the archetypal activity is shown by ADAM17 (known as TNF-α-converting-enzyme, TACE), which is involved in immune and inflammatory response trough activation of TNF-α and plays a relevant role in the development via EGFR activation (Blobel, 2005). ADAM10 is the main ADAM sheddase involved in Regulated Membrane Proteolysis (RIP), the latter being defined as a pathway characterized by an ectodomain shedding on transmembrane protein followed by a cleavage within membrane itself, with critical role in Notch/Delta and Eph/ephrin signaling (Edwards et al., 2008, Saftig and Hartmann, 2005). In this context, ADAMs seem to be involved in neurogenesis, axon extension, adipogenesis and lung, heart and pancreas morphogenesis (Tousseyn et al., 2006, Van Goor et al., 2009).

Furthermore, ADAM family has been implicated in a number of human diseases, such as cancer, asthma, infection and inflammation, neurodegeneration, thus representing attractive targets for novel therapies (Mochizuki and Okada, 2007) (Table 1). As a matter of fact, several ADAMs have been associated with cancer development and progression; for example ADAM12 is upregulated in hematologic, breast and gastric malignancies (Carl-McGrath et al., 2005, Lendeckel et al., 2005, Wu et al., 1997) and ADAM10 is highly expressed in pheochromocytoma and neuroblastoma (Yavari et al., 1998). ADAMs involvement in tumor biology can be explained by different mechanisms, since (i) ADAMs (i.e., ADAM9) could cleave ECM components, such as laminin, and promote cell invasion, similarly to MMPs; (ii) the shedding of adhesion molecules could affect cell adhesion to vasculature; (iii) the shedding of growth factors and their receptors may alter cell growth, as documented for ADAM17 and TNF-α in breast cancer (Kenny and Bissell, 2007, Mazzocca et al., 2005, Tousseyn et al., 2006). The shedding of adhesion molecules directly links ADAMs with inflammatory response, being involved in leukocyte recruitment (Garton et al., 2006, Hafezi-Moghadam and Ley, 1999, Schulz et al., 2008). Linkage studies have also demonstrated that ADAM33 is a candidate asthma-susceptibility locus, even though its function in asthma is unknown (Van Eerdewegh et al., 2002). Interestingly, the identification of ADAM9, ADAM10 and ADAM17 as α-secretases, involved in non-amyloidogenic processing of β-amyloid precursor protein (APP), highlights a new therapeutical approach for Alzheimer’s disease based on the modulation of ADAMs functional profile (Fahrenholz and Postina, 2006, Kojro and Fahrenholz, 2005).

ADAMTS (a disintegrin and metalloprotease with thrombospondin motif) are a group of proteins closely related to ADAMs (see for a review Apte et al., 2009; Jones and Riley, 2005, Li and Liu, 2010, Porter et al., 2005, Salter et al., 2010, Shiomi et al., 2010, Tortorella et al., 2009, Wagstaff et al., 2011).

Unlike ADAMs, ADAMTS are secreted proteins and possess: (i) a thrombospondin type-like (TS) repeat between the disintegrin-like and the cysteine-rich domain; (ii) several thrombospondin-like repeats in the C-terminal region, which seem to be important to bind ECM components (Apte, 2009, Hashimoto et al., 2004, Kuno et al., 2000). These enzymes play roles in development, angiogenesis and coagulation and their dysregulation have been implicated in many disease processes, such as inflammation, cancer, arthritis and atherosclerosis (Li and Lu, 2010) (Table 1). ADAMTS13 has been identified as the von Willebrand factor (VWF)-cleaving protease, whose substrate is a carrier protein for clotting factor VIII, which mediates platelet adhesion to areas of vascular damage (Fujikawa et al., 2001, Levy et al., 2001, Sadler et al., 2000). ADAMTS13 deficiency, determined by anti-ADAMTS13 autoantibody formation or gene mutations, can lead to thrombotic thrombocytopenic purpura (TPP), a condition characterized by microvascular thrombosis with renal failure, anemia and neurological disorder (Levy et al., 2001, Furlan, 1996). In addition, members of this family (such as ADAMTS1 and ADAMTS8) show a powerful angio-inhibitory activity, since they suppress fibroblast growth factor-2 and vascular endothelial growth factor (VEGF)-mediated angiogenic effect on endothelial cells (Vazquez et al., 1999). Mutations in ADAMTS1 have been also associated with an increased risk of coronary artery disease and ADAMTS4, ADAMTS7 and ADAMTS8 have been implicated in atherosclerotic plaque formation (Moriguchi-Goto et al., 2009, Sabatine et al., 2008, Wågsäter et al., 2008). A subgroup of ADAMTS, also referred as “aggrecanases” (i.e., ADAMTS4 and ADAMTS5), have been involved in the degradation of the aggrecan, which forms a major component of cartilage and plays a key role in protecting collagen from degradation (Malfait et al., 2002, Pratta et al., 2003). In this context, several recent discoveries have connected ADAMTS to arthritic disease, rendering these enzymes an important target in arthritis treatment (Li and Liu, 2010).

Astacins family includes several hundred protein detected in species ranging from hydra to humans (for a review see Ge and Greenspan, 2006, Hopkins et al., 2007, Sterchi et al., 2008).

In humans, there are six astacin genes, including two meprins, three bone morphogenetic protein1 (BMP1)/Tolloid like (TLD) proteases and one ovastacin (Sterchi et al., 2008) (Table 1). BMP1 was shown to provide the procollagen C-protease activity involved in the cleavage of C-propeptide from collagen I–III (Kessler et al., 1996, Li et al., 1996). It has then become the prototype of a small subgroup of the astacin family with a similar protein domain architecture, which includes Tolloid-like 1 and Tolloid-like 2. These enzymes play a key role in ECM formation and development through the processing of a variety of precursor proteins in mature functional form (such as procollagen V, VII, XI and laminin 5) and the activation of a subset of transforming growth factor-β (TGF-β) proteins. The multiple roles of BMP1/TLD-related proteins in collagen fibrillogenesis render them interesting anti-fibrotic targets and their inhibition represents a possible approach for the treatment of muscular dystrophies (Hopkins et al., 2007, Wolfman et al., 2003). Meprin proteins are distinguished from other astacins since they include a transmembrane domain and have been discovered only in vertebrates. Meprin subunits α and β cleave a variety of biologically active peptides; in particular, we want to point out gastrin and cholecystokin on one side (which are substrates for meprin β) and substance P and many cytokines on the other side (which are substrates for meprin α, see Sterchi et al., 2008). Meprins are expressed abundantly in epithelial cells of kidney, intestine and skin and recently a number of studies indicate their potential functions in pathological conditions, such as acute and chronic renal failures, diabetic nephropathy, colon carcinoma (Bylander et al., 2008, Lottaz et al., 1999, Red Eagle et al., 2005).

M13 family is group of neutral endopeptidases including neprilysin (NEP), endothelin-converting enzyme (ECE1), endothelin-converting-enzyme-like 1 (ECEL1), the erythrocyte surface antigen KELL and the PHEX gene product (for a review see Kiryu-Seo and Kiyama, 2004, Lee et al., 2000, Turner, 2003, Turner and Nalivaeva, 2006). They are involved in a great number of biological processes, such as neurotransmission, reproduction, cancer progression, control of blood pressure; therefore, they are considered potential therapeutic targets in cardiovascular and inflammatory disorders (Bland et al., 2008, Turner et al., 2001) (Table 1). M13 enzymes display a short N-terminal cytoplasmic domain, a single transmembrane helix and a C-terminal extracellular domain containing the active site and they are generally selective inhibited by Streptomyces product phosphoramidon (Emoto and Yanagisawa, 1995, Turner and Nalivaeva, 2006).

NEP involvement in the inactivation of a variety of physiologically active peptides (such as enkephalin, substance P, bradykinin, oxytocin, neurotensin, bombesin, atrial-natriuretic-peptide (ATR) and β-amyloid) reflects its broader spectrum of physiopathological functions. It is now accepted that NEP functions in the turn off of neuropeptide signals (as for enkephalins) in a fashion similar to acetylcholinesterase at cholinergic synapses. It is located on pre- and post-synaptic membranes and on axonal membrane, where it inactivates the neuropeptide release, acting after their interaction with respective receptors (Matsas et al., 1983, Roques et al., 1980, Turner, 2003). Similarly to angiotensin-converting-enzyme (ACE), NEP inactivates ATR and thus enhances vasodilatation and natriuresis. NEP/ACE inhibitors, the so called “vasopeptidase inhibitors”, are considered a novel therapeutic approach in hypertension, heart and renal disease treatment (Bralet and Schwartz, 2001, Kenny and Stephenson, 1988). Recently, a third class of inhibitors, also including the ECE inhibitor, has been developed: the dual and triple inhibitors, in addition to their ability to effectively lower blood pressure in hypertensive patients, also display antinflammatory and antifibrotic activities. However, this therapy is not free of concerns, since clinical data suggest that the incidence of angioedema may increase with vasopeptidase inhibition (Campbell, 2003, Daull et al., 2007, Quaschning, 2005). Possible NEP implication in cancer mechanism has been postulated on the basis of the NEP identity with the common acute lymphoblastic leukemia antigen CD10, a leukemia associated antigen expressed in lymphoid precursors and germinal B cells, and of an alteration of its expression and activity in a variety of malignancies (Carrel et al., 1983, Tran-Paterson et al., 1989). In particular, NEP plays a pivotal role in the development and progression of androgen-independent-prostate cancer (PC) (Osman et al., 2004, Papandreou et al., 1998, Usmani et al., 2000), since its substrates, such as bombesin and endothelin-1, are implicated at various stages of PC (Albrecht et al., 2004, Freedland et al., 2003). In recent years, NEP has also emerged as an important tumor suppressor gene product and its biological role has been not only related to its enzymatic function, but also to a direct protein–protein interaction (Sumitomo et al., 2005). For example, NEP cytoplasmic tail directly associates with the tumor suppressor PTEN, leading to a negative regulation of downstream cell growth and cell survival pathways, thereby regulating Akt/PKB signaling (Sumitomo et al., 2004). In vitro and in vivo evidences show NEP involvement in β-amyloid (βA) catabolism and NEP is now considered one of the most important proteases targeting βA in the extracellular space, raising the concept of its use as therapeutic target for Alzheimer’s disease (Hersh and Rodgers, 2008, Iwata et al., 2000, Kanemitsu et al., 2003).

NEP homologue ECE1 has been also characterized as an Aβ-degrading enzyme that appears to act intracellularly, thus limiting the amount of Aβ available for secretion (Eckman et al., 2001, Eckman et al., 2003, Shirotani et al., 2001). ECE1 is also known to catalyze the final step in the biosynthesis of the potent endogenous vasoconstrictor peptide, endothelin-1, which acts in a paracrine fashion to regulate vascular tone (Matsumura et al., 1990, Xu et al., 1994). Since the upregulation of ET-1/ECE1 is present at different stages of atherosclerotic plaque evolution, it has been also suggested as a target in atherosclerosis therapy (Ihling et al., 2001, Ihling et al., 2004). A number of other peptides are cleaved in vitro by ECE1, such as substance P, neurotensin and bradykinin, even though is not clear whether these peptides are its physiological substrates (Turner et al., 2001). Despite the structural similarities between ECEL1, ECE and NEP, ECEL1 does not cleave ECE and NEP substrates and its physiological function and substrate specificity remain unknown (Kiryu-Seo et al., 2000, Turner et al., 2001). ECEL1, specifically expressed in neurons of the central and peripheral nervous system since early developmental stages, seems to play an important role in neuronal development (Nagata et al., 2006). ECEL1 expression has been also highly associated with nerve injury in CNS and PNS, since peripheral and optic nerve transections induce ECEL1 expression in nerve-injured neurons (Kato et al., 2002, Kiryu-Seo et al., 2000).

Mutations in the PHEX gene have been identified as responsible for X-linked hypophosphatemic rickets (XLH), the most common form of inherited rickets characterized by growth retardation and rachitic and osteomalacic bone disease (Sabbagh et al., 2000, Tenenhouse, 1999). Although no endogenous substrates for PEX protein have been identified, it has been suggested that PEX could inactivate paracrine or autocrine factors involved in bone and teeth mineralization and/or circulating factors which mediate renal phosphate reabsorption and vitamin D metabolism (Lipman et al., 1998, Tenenhouse, 1999).

Kell protein is a component of the highly polymorphic Kell/XK complex, expressing over 25 antigens, that can induce severe reactions in mismatched blood-transfused patients and severe fetal anemia in sensitized mothers (Lee et al., 2000). The physiological functions of Kell and XK have not been fully elucidated, but Kell is a zinc endopeptidase with endothelin-3-converting enzyme activity and XK has the structural characteristics of a membrane transporter (Redman et al., 1999, Sha et al., 2006).

M41family includes paraplegin and its homologous AFGR3L2 (Table 1) (for a review see Rugarli and Langer, 2006, Salinas et al., 2008). Paraplegin is part of the mitochondrial AAA + protein complex which forms cylindrical hexamers on the inner mitochondrial membrane. It is implicated in the cleavage of the mitochondrial targeting sequence, in ribosome maturation, in the degradation of proteins misfolded after mitochondrial membrane transport and antioxidant defense (Esser et al., 2002, Karlberg et al., 2009, Koppen et al., 2007, Nolden et al., 2005). Mutations in paraplegin gene (SPG7) bring about around 5% of autosomal recessive hereditary spastic paraplegia (HSP), an heterogeneous group of conditions characterized by the presence of lower limb plastic and weakness (Rugarli and Langer, 2006, Salinas et al., 2008). HSP-related mutations in SPG7-gene are associated to axonal degeneration and correlate with the onset of motor impairment (Ferreirinha et al., 2004). Recent investigations show that also AFGR3L2, which forms supercomplex with paraplegin on the inner mitochondrial membrane, is essential for axonal development (Maltecca et al., 2008). Interestingly, genetic and functional data demonstrate that missense mutations of AFGR3L2 lead to dominant hereditary spinocerebellar ataxia type 28 (SCA28), which is a neurological disorder characterized by cerebellar dysfunction related to Purkinje cell degeneration (Di Bella et al., 2010). This result highlights the emerging concept of mitochondrial quality control machinery in protecting human cerebellum from neurodegeneration (Di Bella et al., 2010).

Pappalysin family includes the pregnancy-associated plasma protein-A (PAPPA) and pregnancy-associated plasma protein-E (PAPPA2) (Table 1) (for a review see Boldt and Conover, 2007, Conover, 2010, Consuegra-Sanchez et al., 2009a, Kirkegaard et al., 2010). PAPPA, originally isolated as one of the proteins synthesized in the placenta, circulating at high concentrations in pregnant women, is commonly used as biochemical marker in the screening of Down’s syndrome during first-trimester of pregnancy (Lin et al., 1974, Van Heesch et al., 2010, Wald et al., 1999). PAPPA seems to be a critical determinant of growth and development through the proteolysis of insulin-growth-factor-binding proteins (IGFBPs), which bind IGFI and IGFII, thus preventing their interaction with IGF receptors (Oxvig, 2001). PAPPA-mediated IGFBP cleavage “releases” IGF for receptor activation, modulating the local availability of IGF (Byun et al., 2001, Durham et al., 1994, Laursen et al., 2000). Emerging preclinical, clinical and histopathological evidences sustain that PAPPA may serve as a marker of cardiovascular risk, reflecting the atherosclerotic plaque instability (Bayes-Genis et al., 2001, Lund et al., 2003, Consuegra-Sanchez et al., 2009a). In this context, it has been proposed that cell-associated PAPPA, enhancing local IGF actions, could amplify atherosclerosis plaque formation (Conover, 2010). Little is known on PAPPA1 homologue, PAPPA2, even though in a recent study the analysis of tissue expression patterns and biological consequences of KO gene indicate distinct physiological roles for PAPP-A2 and PAPP-A in mice (Conover et al., 2011).

Farnesylated-protein converting enzyme 1, also known as ZMPSTE24, is a membrane protease with seven predicted membrane spans (for a review see Barrowman and Michaelis, 2009, Liu and Zhou, 2008, Young et al., 2006). It performs a critical step in the processing of prelamin A in lamin A, a nuclear intermediate filament which provides nuclear structure and participates to heterochromatin organization and cell cycle control, removing the farnesyl tail of prelamin A (Mattout et al., 2006, Ramirez et al., 2007). ZMPSTE24 is associated directly and indirectly to human progeroid disorders (Capell and Collins, 2006, Young et al., 2005). The failure of prelamin A cleavage by ZMPSTE24 due to the absence of the cleavage site results in one form of laminopathy, Hutchinson–Gilford Progeria Syndrome (HGPS), which appear to mimick accelerated aging, being characterized by bone abnormalities, slow growth and atherosclerosis (Capell et al., 2007). Mutations in ZMPSTE24 gene also induce two secondary laminopathies, Restrictive Dermopathy (RD) and Mandibuloacral Dysplasia (MD) (Capell and Collins, 2006). RD generally results in death in uterus, since it is associated to total loss of ZMPSTE24 function, while MD is a mild condition with one partially active ZMPSTE24 allele, characterized by skeletal abnormalities, such as hypoplasia of mandible, cutaneous atrophy and progeroid feature (Agarwal et al., 2003a, Agarwal et al., 2003b, Ahmad et al., 2010, Denecke et al., 2006, Lombardi et al., 2008, Miyoshi et al., 2008).

Section snippets

M10 family

M10 family includes human Zn-endopeptidases known as “Matrix metalloproteinases” (MMPs) (see Table 2), which are involved in a great variety of physiopathological processes like skeletal growth and remodeling, wound healing, cancer, arthritis and multiple sclerosis (Bafetti et al., 1998, Hirose et al., 1992, Matrisian et al., 1986, Vu et al., 1998, Wysocki et al., 1993, Nagase and Woessner, 1999, Sternlicht and Werb, 2001, Vu and Werb, 2000, Opdenakker et al., 2003, Fingleton, 2007).

Since MMPs

Collagenases

The name of this class of MMPs refers to the capability of its components to enzymatically process native collagen molecules without unwinding the triple helical assembly of the substrate. Their structural arrangement in the active enzyme is made by a catalytic domain (where the catalytic Zn2+ is present and the proteolytic cleavage takes place) and a hemopexin-like domain, made by a typical four-blade propeller structure; they are connected by an intermediate hinge region, which seems to play

Gelatinases

Gelatinases is a class of MMPs historically defined according to their affinity for denatured collagen (i.e., gelatin). This class includes two members, namely (i) gelatinase A or MMP-2 (72 and 62 kDa for the pro-enzyme and the active enzyme, respectively); (ii) gelatinase B or MMP-9 (92–85-82 kDa for the pro-enzyme, the intermediate form and active enzyme, respectively) (see Table 2).

The domain composition shares with other MMPs the presence of a pro-peptide, a highly conserved N-terminal

Stromelysins

The class of stromelysins encompasses three enzymes, namely MMP-3 (stromelysin-1), MMP-10 (stromelysin-2), and MMP-11 (stromelysin-3).

The overall structure includes the catalytic domain, the hemopexin-like domain and the pro-peptide, but significant differences with other soluble MMPs are also found. In particular, MMP-11 exhibits an additional pro-protein convertase recognition sequence, which envisages a peculiar activation mechanisms (Visse and Nagase, 2003).

Although stromelysins have been

Matrilysins

Matrylisin family includes two enzymes: MMP-7 (also known as Pump-1) and MMP-26 (De Coignac et al., 2000, Quantin et al., 1989). These enzymes display significant sequence similarities with collagenases and stromelysins, even though the domain composition lacks the hemopexin-like domain (see Fig. 1) (Uria and Lopez-Otin, 2000).

A vast deal of knowledge defines a relevant physiopathological role for MMP-7, whereas biological aspects of MMP-26 should be restricted to extracellular matrix turn-over

Membrane type-MMPs

The first human MT-MMP (MT1-MMP/MMP-14) (Sato et al., 1994) was cloned by a reverse transcriptase-polymerase chain reaction (RT-PCR) from the RNA of placental tissue. Later on, additional studies, focused on MT-MMPs, led to the discovery of five more members of this family, namely MT2-MMP (MMP-15), MT3-MMP (MMP-16), MT5-MMP (MMP-24) and two additional members, MT4-MMP (MMP-17) and MT6-MMP (MMP-25), which are anchored to the plasma membrane via a glycosylphosphatidylinositol (GPI) domain (Zucker

Structure and function

MMP-12, also called macrophage metalloelastase, is the most active MMP against elastin (Shapiro, 1998). MMP-12 is a 54 kDa proenzyme that is processed into a 45 kDa and then a 22 kDa active forms (Shapiro et al., 1992). The human gene, which is designated human macrophage metalloelastase, produces a 1.8-kb transcript encoding a 470-amino acid protein that is 64% identical to the mouse protein (Shapiro et al., 1992). MMP-12 is predominantly expressed in alveolar macrophages, in airway epithelial

Acknowledgements

The authors are very thankful to Profs. Paolo Ascenzi, Hideaki Nagase, Ghislain Opdenakker, Chris M. Overall, Tayebeh Pourmotabbed, James P. Quigley, Harald Tschesche and Philippe van den Steen for several fruitful discussions during the writing of this review.

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