Metalloprotease Regulator Proteins

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 Metalloprotease Regulator Proteins Background

Proteinases comprise six different families based on the nature of the chemical group responsible for catalytic activity: the serine, cysteine, aspartic, threonine, glutamic, and metalloproteinases. Metalloendopeptidases are present across all kingdoms of living organisms; they are ubiquitous and widely involved through their ability either to extensively degrade proteins or to selectively hydrolyze specific peptide bonds. They must be subjected to exquisite spatial and temporal control to prevent this vast potential from becoming destructive. These enzymes are mostly zinc-dependent and the majority of them, named zincins, possess a short consensus sequence, HEXXH, with the two histidines acting as ligands of the catalytic zinc and the glutamate as the general base. A subclass of the zincins is characterized by a C-terminally elongated motif, HEXXHXXGXXH/D, with an additional strictly conserved glycine and a third zinc-binding histidine or aspartate. Other shared characteristics are an invariant methionine-containing Met-turn beneath the catalytic metal and a further C-terminal helix in the lower subdomain. All these structural features identify the metzincin clan of metalloendopeptidases. The present study focuses on the metzincins, which play a major role during various physiologic processes and numerous diseases. The metzincin subgroup is further divided into serralysins, astacins, matrixins, and adamalysins.



The matrixins comprise the matrix metalloproteases, or MMPs. All MMPs, except for the membrane type (MT-) MMPs, are secreted as latent pro-forms. The pro-domain is followed by the catalytic domain, which is connected through a linker to a C-terminal haemopexin-like domain; in the MT-MMPs, the polypeptide chain possesses an additional 75- to 100-residue extension, which forms a transmembrane helix and a small cytoplasmatic domain. In both gelatinases (MMP-2 and MMP-9), the catalytic domains have an insert comprising three fibronectin-related type II modules conferring gelatin and collagen binding. Adamalysins are similar to the matrixins in their metalloprotease domains, but contain a unique integrin receptor-binding disintegrin domain. It is the presence of these two domains that give the ADAMs their name (a disintegrin and metalloprotease). The domain structure of the ADAMs consists of a prodomain, a metalloprotease domain, a disintegrin domain, a cysteine-rich domain, an EGF-like domain, a transmembrane domain, and a cytoplasmic tail. The adamalysin subfamily also contains the class III snake venom metalloproteases and the ADAM-TS family, which although similar to the ADAMs, can be distinguished structurally by the presence of thrombospondin repeats.

The members of the MMP family are collectively capable of digesting all known ECM macromolecules, such as interstitial and basement membrane collagens, proteoglycans, fibronectin and laminin. Therefore, MMPs are implicated in connective tissue remodeling processes associated with embryonic development, pregnancy, growth and wound healing. Their role in angiogenesis, tumor growth and metastasis has been extensively investigated and described. Their relevance in cancer beyond the classical role of ECM disruption in the later, invasive stage of the disease has also been investigated. Proteolytic processing of bioactive molecules by MMPs contributes to the formation of a complex microenvironment that promotes malignant transformation in early stages of cancer. These additional functions mediated by MMPs include activation of growth factors, suppression of tumor cell apoptosis, destruction of chemokine gradients developed by host immune response, or release of angiogenic factors. The role of MMPs in angiogenesis is also dual and complex. The relevance of these enzymes as positive regulators of tumor angiogenesis has been largely demonstrated. Thus, several pro-angiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) or transforming growth factor-P (TGF-(3) are induced or activated by these enzymes, triggering the angiogenic switch during carcinogenesis and facilitating vascular remodeling and neovascularization at distant sites. MMP expression and activity are regulated by precise mechanisms in both physiological and pathological conditions. Despite the complexity of MMP regulation, three major levels of endogenous control should be mentioned: gene transcription, proenzyme activation, and inhibition of enzymatic activity.



Ectodomain shedding (or "sheddase" activity) plays an important role in the embryonic development, the regulation of inflammatory responses, and the regulation of the establishment and maintenance of new capillary formation. It has also been implicated in the pathology of Alzheimer's disease, Parkinson's disease and cancer cell invasion.

The ADAMs are sheddase members of the adamalysin family of the metzincin subclan of Zn-dependent metalloproteases. This family also includes snake venom metalloproteases (SVMPs) and ADAMTS proteins. Excluding pseudogenes, public databases list 20 genes encoding human ADAMs. All ADAMs contain (from N- to C-terminus): pro, metalloprotease, disintegrin, cycteine-rich, spacer, transmembrane and cytoplasmic tail domains. In contrast to the SVMP and ADAMTS proteins, only 60% of ADAMs contain a catalytic signature motif (HExGHxxGxxHD), all of which have been tested to be proteolytically active. The prodomain is thought to work as an intramolecular chaperone controlling folding of the catalytic domain. It maintains the protease domain in a latent phase and it may also influence intracellular trafficking. Most ADAM pro-domains are removed by proprotein convertases (e.g., furin) in the secretory pathway. ADAM8 and ADAM28 have been shown to undergo autocatalytic processing.

ADAMs are the major 'sheddases' or proteases responsible for ectodomain shedding. Substrates that can be shed by ADAMs include signaling ligands, receptors for signaling cell adhesion molecules and other proteins located in the extracellular spaces. Shedding can be constitutive, but it is generally enhanced by stimuli such as from G protein coupled receptors. ADAMs shed membrane-anchored substrates by cleaving their juxtamembrane region. The released ligand then can bind to cell surface receptors initiating autocrine or paracrine extracellular signaling pathways. The shedding of a cell surface receptor could also modulate the extracellular signaling response.

ADAMs also participate in intracellular signaling. This was first shown through demonstrating the role of the fly ADAM10 in the lateral inhibition that leads to the selective differentiation of neuronal cells through the Notch signaling pathway in Drosophila. The ectodomain of the Notch cell surface receptor is shed by ADAM 10, followed by a subsequent cleavage of the transmembrane domain by presenilin. The resulting fragment leaves the membrane and travels to the nucleus to influence gene transcription.