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University of Groningen the Biology of Adams in Renal Disease University of Groningen The biology of ADAMs in renal disease Melenhorst, Wynand Bernhard Willem Henderik IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2009 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Melenhorst, W. B. W. H. (2009). The biology of ADAMs in renal disease. s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 27-09-2021 2 ADAMALYSINS IN BIOLOGY AND DISEASE Harry van Goor1 Wynand Melenhorst1 Anthony Turner2 Stephen Holgate3 1. Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, the Netherlands 2. Division of Infection, Inflammation and Repair, Southampton General Hospital, Southampton, United Kingdom 3. Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom. Journal of Pathology 2009, in press Chapter 2 Abstract ADAMs (A Disintegrin And Metalloprotease) are membrane-bound enzymes, capable of shedding a multitude of proteins from the surface of the cell. They are therefore considered crucial modulators of physiological and pathophysiological processes. The structure and function of ADAMs is related to those of a family of snake venom metalloproteases which also possess a potential adhesion domain as well as a potential protease domain. Mammalian ADAMs are involved in various biological and disease-related processes like cell-cell fusion, adhesion, and intracellular signalling. Functional involvement has been described in sperm-egg binding and fusion, trophoblast invasion and matrix degradation during pregnancy, angiogenesis, and neovascularization. Clinically, ADAMs are implicated in pathological processes including cancer, inflammation, neurodegeneration and fibrosis through shedding of the apoptosis-inducing FAS ligand, cytokines and growth factors. A second group of proteins within the ADAM family has recently been discovered. These contain several thrombospondin-like repeats in their C-terminal regions, in the absence of the transmembrane domain known to be present in ADAMs. These proteins were called the ADAMTS (ADAM with ThromboSpondin domains) family. The relevance of ADAMTS enzymes has become evident in patients with a deficiency in ADAMTS-13, a von Willebrand factor cleaving protease. These patients develop thrombotic thrombocytopenic purpura, a devastating thrombotic disorder caused by widespread microvascular thrombi composed of platelets and von Willebrand factor (VWF). In the present review, we will concentrate on the genetic, developmental, functional and disease-related aspects of ADAMs and ADAMTS. Finally we will discuss the perspectives of the therapeutical potential of ADAMs in disease. 20 Adamalysins in Biology and Disease Introduction ADAMs (mnemonic for A Disintegrin And Metalloprotease) are an intriguing group of membrane- bound enzymes that belong to a larger zinc-dependent superfamily called the metzincins. The structure and function of ADAMs is closely related to those of a family of snake venom metalloproteases, which are responsible for the haemorrhage effects and massive tissue necrosis commonly seen after snakebites. These damaging effects are inflicted by massive destruction of the extracellular matrix surrounding capillaries in conjunction with the inhibition of platelet aggregation by disintegrins, which block the function of adhesion molecules and are accompanied by severe inflammation1. These deleterious actions of ADAMs clearly reveal their capacity to modulate (patho)-physiological processes. ADAMs are unique in the sense that they possess a potential adhesion domain as well as a potential protease domain. Mammalian ADAMs are engaged in cell-cell fusion, adhesion, and intracellular signalling. These functions are illustrated by their involvement in various biological processes, like sperm-egg binding and fusion, trophoblast invasion and matrix degradation during pregnancy, angiogenesis, and neovascularization. The clinical significance of ADAMs is evidenced by their implication in pathological processes including cancer, inflammation, neurodegeneration and fibrosis through shedding of the apoptosis-inducing FAS ligand, cytokines and growth factors. More recently, the complexity of the ADAM family of metalloproteases with disintegrin domains has grown considerably after the description of an ADAM-related protein containing several thrombospondin-like repeats in its C- terminal region, in the absence of the transmembrane domain known to be present in ADAMs2. This protein was named ADAMTS-1 (ADAM with ThromboSpondin domains), and is the first member of a new family of 19 metalloproteases with structural and functional properties related to, but distinct from, ADAMs3;4. The clinical relevance of ADAMTS enzymes is most clearly seen in patients with a deficiency in ADAMTS-13, a von Willebrand factor cleaving protease, who develop thrombotic thrombocytopenic purpura, a devastating thrombotic disorder caused by widespread microvascular thrombi composed of platelets and von Willebrand factor (VWF). In this review, we discuss the genetic, developmental, functional and disease-related aspects of ADAMs and ADAMTS with recommendations for therapeutic intervention. Structural and biochemical aspects of ADAMs The first members of the ADAM family of disintegrin-metalloproteases to be discovered (ADAMs 1 and 2) were identified as being critical for the fertilization process5;6. Since that time the family has expanded considerably and now comprises 40 genes in various species and 23 known ADAM genes in humans. A current list of all ADAMs genes and the associated proteins is available on the University of Virginia website: http://people.virginia.edu/~jw7g/. Only around half of the known ADAMs are functionally active as metalloproteases, since significant members of the family lack one or more critical catalytic residues. The protease domain is implicated in many protein- shedding events from the cell-surface, including the release of growth factors, cytokines, receptors and adhesion molecules. The roles of the catalytically inactive ADAMs are mostly 21 Chapter 2 unknown, but could range from acting as peptide-binding receptors, to mediating cell-cell interactions, influencing cell adhesion or migration and mediating cell-signalling through other functional domains of the protein, particularly the cytoplasmic tail. We will principally focus on the protease-active ADAMs since, for these, there are clearer indications of their (patho)-physiological involvement. Nevertheless, unraveling the substrate repertoire of any individual ADAM or identifying which of the numerous ADAM proteins cleave a particular protein substrate remains a challenging task although newer strategies are emerging to deal with these questions7. These include the use of transgenic models, cellular over-expression or knock-down of individual ADAMs, and the use of ADAM-specific inhibitors. Structurally, ADAMs are single-span, transmembrane proteins that comprise a pro-domain, a zinc metalloprotease domain facing extracellularly, a disintegrin domain, a cysteine-rich region, an EGF-like sequence, a transmembrane region and a cytoplasmic tail (Figure 1). The proteins are related to the matrix metalloproteases (MMPs) and MMP inhibitors often also inhibit the activities of ADAMs. The pro-domain uses a “cysteine-switch” mechanism to hold the catalytic zinc ion and the protease domain in a latent state and to facilitate correct folding of the protein during biosynthesis. However, in the case of ADAM17, the only role for the prodomain appears to be in stabilizing the protein against proteolytic degradation during its biosynthesis and trafficking8. The structures of the catalytic domains of ADAM17 and ADAM33 reveal a central five-stranded b- sheet surrounded by five a-helices with a conserved methionine residue constituting the so-called “methionine-turn”, a distinctive feature of the metzincin proteases9;10. Not all ADAMS are enzymatically active since some lack the characteristic catalytic zinc-binding signature. The related ADAMTS family differs from the ADAMs in lacking the EGF-like sequences and the transmembrane domains and hence function as secreted proteins. They all retain the metalloprotease domain as well as a disintegrin-like domain. The precise functions of the disintegrin-like domain remain unclear as to whether the interactions with integrins seen in vitro are physiologically relevant. Additionally, ADAMTS proteins contain a variable spacer region and one or more C-terminal thrombospondin (TS) repeat motifs. Originally identified as playing a role in procollagen (procollagen N-endopeptidase, ADAMTS2) and aggrecan (ADAMTS4) processing,
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