ADAMs: focus on the protease domain

doi:10.1016/S0955-0674(98)80042-2

Current Opinion in Cell Biology

Volume 10, Issue 5, October 1998, Pages 654-659

https://doi.org/10.1016/S0955-0674(98)80042-2 Get rights and content

Abstract

ADAMs are proteins containing a disintegrin and metalloproteinase domain. Several important insights were provided in the past year regarding ADAM metalloproteinases: ADAM 10 was implicated in the Notch signaling pathway. ADAM 17 was shown to be the long sought after tumor necrosis factor-α convertase and the crystal structure of its metalloproteinase domain was determined.

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It was realized in the 1990s that some membrane proteins such as TNFα, both TNF receptors, ligands of the EGF-R and the Interleukin-6 receptor are proteolytically cleaved and are shed from the cell membrane as soluble proteins. The major responsible protease is a metalloprotease named ADAM17. So far, close to 100 substrates, including cytokines, cytokine receptors, chemokines and adhesion molecules of ADAM17 are known. Therefore, ADAM17 orchestrates many different signaling pathways and is a central signaling hub in inflammation and carcinogenesis. ADAM17 plays an important role in the biology of Interleukin-6 (IL-6) since the generation of the soluble Interleukin-6 receptor (sIL-6R) is needed for trans-signaling, which has been identified as the pro-inflammatory activity of this cytokine. In contrast, Interleukin-6 signaling via the membrane-bound Interleukin-6 receptor is mostly regenerative and protective. Probably due to its broad substrate spectrum, ADAM17 is essential for life and most of the few human individuals identified with ADAM17 gene defects died at young age. Although the potential of ADAM17 as a therapeutic target has been recognized, specific blockade of ADAM17 is not trivial since the metalloprotease domain of ADAM17 shares high structural homology with other proteases, in particular matrix metalloproteases. Here, the critical functions of ADAM17 in IL-6, TNFα and EGF-R pathways and strategies of therapeutic interventions are discussed.
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Changes in expression or activation of various metalloproteases including matrix metalloproteases (Mmp), a disintegrin and metalloprotease (Adam) and a disintegrin and metalloprotease with thrombospondin motif (Adamts), and their endogenous inhibitors (tissue inhibitors of metalloproteases, Timp), have been shown to be critical for ovulation in various species from studies in past decades. Some of these metalloproteases such as Adamts1, Adamts9, Mmp2, and Mmp9 have also been shown to be regulated by luteinizing hormone (LH) and/or progestin, which are essential triggers for ovulation in all vertebrate species. Most of these metalloproteases also express broadly in various tissues and cells including germ cells and somatic gonad cells. Thus, metalloproteases likely play roles in gonad formation processes comprising primordial germ cell (PGC) migration, development of germ and somatic cells, and sex determination. However, our knowledge on the functions and mechanisms of metalloproteases in these processes in vertebrates is still lacking. This review will summarize our current knowledge on the metalloproteases in ovulation and gonad formation with emphasis on PGC migration and germ cell development.
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Xanthones are important chemical class of bioactive products that confers therapeutic benefits. Of several xanthones, mangiferin is known to be distributed widely across several fruits, vegetables and medicinal plants. Mangiferin has been shown to exert neuroprotective effects in both in-vitro and in-vivo models. Mangiferin attenuates cerebral infarction, cerebral edema, lipid peroxidation (MDA), neuronal damage, etc. Mangiferin further potentiate levels of endogenous antioxidants to confer protection against the oxidative stress inside the neurons. Mangiferin is involved in the regulation of various signaling pathways that influences the production and levels of proinflammatory cytokines in brain. Mangiferin cosunteracted the neurotoxic effect of amyloid-beta, MPTP, rotenone, 6-OHDA etc and confer protection to neurons. These evidence suggested that the mangiferin may be a potential therapeutic strategy for the treatment of various neurological disorders. The present review demonstrated the pharmacodynamics-pharmacokinetics of mangiferin and neurotherapeutic potential in several neurological disorders with underlying mechanisms.
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The isolation and characterization of individual snake venom components is important for a deeper understanding of the pathophysiology of envenomations, for improving the therapeutic procedures of patients, and it also opens possibilities for the discovery of novel toxins that might be useful as tools for understanding cellular and molecular processes. This review provides a summary of the different toxins that have been isolated and characterized from the venoms of Vipera lebetina (Macrovipera lebetina) subspecies Macrovipera lebetina cernovi, Macrovipera lebetina lebetina, Macrovipera lebetina obtusa, Macrovipera lebetina transmediterranea, Macrovipera lebetina turanica, the snake species causing the majority of human envenomings in Central Asia (Middle East) and North Africa. The venoms of these snakes contain proteins belonging to different families: Zn²⁺- metalloproteinases, serine proteinases, L-amino acid oxidase, 5′-nucleotidase, phosphodiesterase, phosphomonoesterase, nucleases, hyaluronidase, phospholipase A2, C-type lectin-like protein, disintegrin, DC-fragment, cystein-rich secretory protein, proteinase inhibitors, nerve growth factor (NGF), vascular endothelial growth factor (VEGF), low molecular weight peptides. Their main biochemical properties, toxic and pharmacological actions have been described. In this review we will provide an overview of the proteins and peptides from the venoms of M. lebetina subspecies, their biochemical, pharmacological and structural features and their role in snake venom toxinology. A lot of contributions have been made for better understandings of these venomous snakes, their venom, and their pharmacological effects. Many of these components are also fascinating models for drug design.
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ADAMs: focus on the protease domain

Abstract

Dev Biol

Cell

J Biol Chem

Cell

Protein Sci

Cell

Science

Nature

Eur Cytokine Network

Proc Natl Acad Sci USA

FASEB J

Proc Natl Acad Sci USA

Cytokine

Br J Haematol

FEBS Lett

Proc Natl Acad Sci USA

Metalloproteinase-disintegrins: links to cell adhesion and cleavage of TNFα and notch

Cell

TNF-α converting enzyme

ADAM metalloproteinases

Human ADAM 12 (meltrin alpha) is an active metalloprotease

J Biol Chem