Structural Determinants of the ADAM Inhibition by TIMP-3: Crystal Structure of the TACE-N-TIMP-3 Complex

Wiśniewska, M.; Goettig, Peter; Maskos, K.; Belouski, Edward; Winters, Dwight; Hecht, Randy; Black, Roy A.; Bode, Wolfram

doi:10.1016/j.jmb.2008.06.088

Cited by 88 publications

(88 citation statements)

References 62 publications

(78 reference statements)

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“…However, substitution of the zinc-binding Asp 362 for a His increases the susceptibility to N-TIMP-3 inhibition. The crystal structure of hADAM-17 in complex with N-TIMP-3 reveals that Glu 65 of N-TIMP-3 interacts with the backbone nitrogen of His 415 , the third zinc ligand of hADAM-17 (27). Because the amino acid side chain of Asp is shorter than that of His, the backbone of the active site Asp 362 in ADAMDEC1 is predicted to be moved closer to the Zn 2ϩ in order to accommodate binding (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…The observed effects lead us to hypothesize that hADAMDEC1 has evolved with the rare active site and the unpaired Cys 392 allowing escape from inhibition by TIMP-3 and ␣2M. (27)). N-TIMP-3 interacts directly with the catalytic Zn 2ϩ through the backbone amino and carbonyl groups of Cys 1 and with the substrate binding pockets through multiple amino acid side chains (as indicated in the figure).…”

Section: Discussionmentioning

confidence: 99%

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Evidence for Restricted Reactivity of ADAMDEC1 with Protein Substrates and Endogenous Inhibitors

Lund

Troeberg

Kjeldal

et al. 2015

Journal of Biological Chemistry

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Background: ADAMDEC1 is an ADAM-like metalloprotease with a rare active site affecting the proteolytic activity. Results: Reconstruction of the ADAMDEC1 active site, based on the ADAM family consensus, increases proteolytic activity and susceptibility for inhibition. Conclusion: Specific structural features may protect ADAMDEC1 from endogenous metalloprotease inhibitors. Significance: ADAMDEC1 has evolved features resulting in narrow substrate specificity and restricted reactivity with endogenous protease inhibitors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Evidence for Restricted Reactivity of ADAMDEC1 with Protein Substrates and Endogenous Inhibitors

Lund

Troeberg

Kjeldal

et al. 2015

Journal of Biological Chemistry

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“…These soluble proteins inhibit matrix metalloproteases and ADAMs by inserting their aminoterminal wedge-shaped cleft into the active site of the enzyme (Wisniewska et al 2008). There are four Timps in mammals; of these, ADAM10 can be inhibited by Timp1 and Timp3, whereas TACE is inhibited only by Timp3 (Murphy 2011).…”

Section: Impact Of Stimuli On Tace Activity On the Plasma Membranementioning

confidence: 99%

Regulation of Receptor Tyrosine Kinase Ligand Processing

Adrain

Freeman

2014

Cold Spring Harbor Perspectives in Biology

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A primary mode of regulating receptor tyrosine kinase (RTK) signaling is to control access of ligand to its receptor. Many RTK ligands are synthesized as transmembrane proteins. Frequently, the active ligand must be released from the membrane by proteolysis before signaling can occur. Here, we discuss RTK ligand shedding and describe the proteases that catalyze it in flies and mammals. We focus principally on the control of EGF receptor ligand shedding, but also refer to ligands of other RTKs. Two prominent themes emerge. First, control by regulated trafficking and cellular compartmentalization of the proteases and their ligand substrates plays a key role in shedding. Second, many external signals converge on the shedding proteases and their control machinery. Proteases therefore act as regulatory hubs that integrate information that the cell receives and translate it into precise outgoing signals. The activation of signaling by proteases is therefore an essential element of the cellular communication machinery.C ells must talk to one another. This principle applies throughout the tree of life: from unicellular bacteria, to the trillions of cells that coordinate to make a mammal. Communication between cells requires dedicated machinery, capable of relaying information across membranes. Transmembrane proteins are therefore essential for signaling. Understanding how this is regulated is paramount. In mammals, receptor tyrosine kinases (RTKs) and their ligands are important examples of such machinery (Schlessinger 2000), controlling many biological processes including development, immunity, tissue repair, and metabolic homeostasis (Ullrich and Schlessinger 1990). They are transmembrane proteins with an extracellular ligand-binding motif and an intracellular kinase domain. As discussed in other chapters, a common mode of RTK activation involves receptor dimerization induced by ligand binding (Lemmon and Schlessinger 2010).Regulated access of ligand to receptor, over distance and time, is key to controlling signaling. Ligands are frequently synthesized as transmembrane forms; when they remain membrane-tethered and cannot diffuse, the range over which they can operate is limited to adjacent cells (Massague and Pandiella 1993; Singh and 1 Present address: Instituto

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“…TACE/ADAM-17 not only cleaves proTNF-α but also releases or sheds other ligands, including TNFR1, TNFR2, the interleukin-6 receptor (IL-6R), members of the membrane-bound epidermal growth factor (EGF) family, the Notch receptor, fractalkine/CX3CL1, L-selectin, and transforming growth factor-α (TGF-α) [19]. TACE/ADAM-17 is, in turn, regulated by another endogenous protein, tissue inhibitor of metalloproteinases-3 (TIMP-3), a competitive inhibitor of TACE/ADAM-17 [20,21].…”

Section: Introductionmentioning

confidence: 99%

Tissue Inhibitor of Metalloproteinase-3 Ameliorates Total Sublethal Hepatic Ischemia/Reperfusion Injury in a Rat Model

Swamy¹

2012

J Transplant Technol

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Orthotopic liver transplantation is the only treatment for end stage liver disease. Recipients outweigh the number of available healthy donor livers, and options for increasing the donor pool have included the use of marginal livers. Transplantation of marginal livers is a known risk factor for the development of primary non-function post-transplant. Although the precise cause of primary non-function is not known, ischemia/reperfusion (I/R) injury has been strongly implicated, and tumor necrosis factor-α (TNF-α) plays a critical role. We utilized a rat I/R model to determine whether treatment with tissue inhibitor of metalloproteinase-3 (TIMP-3) after total sublethal I/R injury improves liver health by preventing the release of active TNF-α. Rats were pre-treated with either TIMP-3 or saline and underwent total warm hepatic ischemia followed by 6, 24, 48 hours or 7 days reperfusion. All rats survived treatment and I/R injury. Serum samples were assayed for TNF-α, interleukin-6 (IL-6), and alanine aminotransferase (ALT). Histology and RT-PCR for TNF-α and TNF-α-converting enzyme [TACE or a disintegrin and metalloproteinase-17 (ADAM-17)] were performed on liver tissues. TIMP-3 treatment resulted in decreased TNF-α and IL-6 levels, and the inhibition occurred at a posttranscriptional level as mRNA expression of TNF-α and TACE/ADAM-17 was not affected. ALT levels reached basal levels in TIMP-3-treated rats more quickly than untreated rats, and livers of treated rats showed mild edema while livers of untreated rats exhibited hepatic collapse, necrosis, and hemorrhage. Our results indicate that TIMP-3 treatment protects the liver from total sublethal I/R injury through a TNF-α-specific pathway.

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Structural Determinants of the ADAM Inhibition by TIMP-3: Crystal Structure of the TACE-N-TIMP-3 Complex

Cited by 88 publications

References 62 publications

Evidence for Restricted Reactivity of ADAMDEC1 with Protein Substrates and Endogenous Inhibitors

Evidence for Restricted Reactivity of ADAMDEC1 with Protein Substrates and Endogenous Inhibitors

Regulation of Receptor Tyrosine Kinase Ligand Processing

Tissue Inhibitor of Metalloproteinase-3 Ameliorates Total Sublethal Hepatic Ischemia/Reperfusion Injury in a Rat Model

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