Crystal structure of RVV‐X: An example of evolutionary gain of specificity by ADAM proteinases

Takeda, Soichi; Igarashi, Tomoko; Mori, Hiromu

doi:10.1016/j.febslet.2007.11.062

Cited by 89 publications

(76 citation statements)

References 21 publications

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“…Despite their divergent nomenclature, accumulating evidence suggests the catalytic domain and Dis-Cys domain are spatially associated within the complete ADAM ectodomain (14,15). Specifically, the crystal structures of ADAM homologs VAP1 (13), VAP2B (16), RVVX (17), and the nonproteolytic ectodomain of human ADAM22 (18) support the notion that ADAM proteins are "C-shaped" (Fig. S1).…”

Section: Adam17 | Antibody Phage Display | Cancer Therapeuticsmentioning

confidence: 65%

Cross-domain inhibition of TACE ectodomain

Tape

Willems

Dombernowsky

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

113

108

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Proteolytic release from the cell surface is an essential activation event for many growth factors and cytokines. TNF-α converting enzyme (TACE) is a membrane-bound metalloprotease responsible for solubilizing many pathologically significant membrane substrates and is an attractive therapeutic target for the treatment of cancer and arthritis. Prior attempts to antagonize cell-surface TACE activity have focused on small-molecule inhibition of the metalloprotease active site. Given the highly conserved nature of metalloprotease active sites, this paradigm has failed to produce a truly specific TACE inhibitor and continues to obstruct the clinical investigation of TACE activity. We report the bespoke development of a specific TACE inhibitory human antibody using "two-step" phage display. This approach combines calculated selection conditions with antibody variable-domain exchange to direct individual antibody variable domains to desired epitopes. The resulting "cross-domain" human antibody is a previously undescribed selective TACE antagonist and provides a unique alternative to smallmolecule metalloprotease inhibition. ADAM17 | antibody phage display | cancer therapeuticsT NF-α converting enzyme (TACE) [a disintegrin and metalloprotease 17 (ADAM17)], is a membrane-bound metalloprotease responsible for cleaving a variety of pathologically significant substrates (1). Initially identified as the enzyme responsible for solubilizing membrane-associated pro-TNF-α (2, 3)-a process subsequently termed "ectodomain shedding," TACE has since proved capable of cleaving epidermal growth factor receptor (EGFR) ligands (4), extracellular Notch1 (5), cell-surface receptors (6), and adhesion molecules (7). As proteolytic cleavage is an indispensable activation event for many of these substrates, TACE has emerged as an attractive therapeutic target for the treatment of cancer (8) and rheumatoid arthritis (9).Preceding the current clinical interest in TACE, members of the related matrix metalloprotease (MMP) family were also considered viable therapeutic targets (10). Despite sound preclinical rational for antagonizing MMPs, early trials of smallmolecule inhibitors (SMIs) failed due to poor inhibitor specificity profiles (11,12). Metalloprotease SMIs exclusively target the catalytic site. This paradigm treats the raw proteolytic capacity of the catalytic site as the only significant target-often with no regard to noncatalytic domains. This catalytic focus forces the selectivity of SMIs to rely exclusively on modest biophysical differences surrounding individual metalloprotease catalytic sites and typically yields inhibitors simply with a bias toward a particular metalloprotease. Macromolecular metalloprotease inhibitors [e.g., tissue inhibitor of metalloproteases (TIMPs) and metalloprotease prodomains] also focus on binding the catalytic site and suffer comparable specificity limitations. The unfortunate simplification of multidomain extracellular proteases to spatially isolated catalytic sites has ignored the potential for noncatal...

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Section: Adam17 | Antibody Phage Display | Cancer Therapeuticsmentioning

confidence: 65%

Cross-domain inhibition of TACE ectodomain

Tape

Willems

Dombernowsky

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

113

108

View full text Add to dashboard Cite

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“…Although currently there are only a few reports of potential exosites in ADAM protease structures (11,31), a recent paper by Tape et al (32) demonstrated that it is possible to achieve selective binding to the ADAM17 ectodomain by an antibody that exploits exosites. Our group recently reported a discovery of a small molecule that inhibits ADAM17 in a non-zinc-binding fashion, which also supports exosite targeting strategies for ADAM17 drug and probe discovery (15).…”

mentioning

confidence: 99%

“…Crystallographic and modeling studies by Takeda et al (10,11), demonstrated the possibility that noncatalytic domains of membrane-bound ADAM17 can contribute to substrate recognition and binding of cell surface proteins, which necessitates studies with substrates that can interact with noncatalytic domains. Cleavage site sequence specificity has been addressed for several members of the ADAM family (12)(13)(14), but most of the substrates utilized for these studies were short (ϳ10 residues) and therefore were likely to interact only with the catalytic domain of ADAMs.…”

mentioning

confidence: 99%

Activity of ADAM17 (a Disintegrin and Metalloprotease 17) Is Regulated by Its Noncatalytic Domains and Secondary Structure of its Substrates

Stawikowska

Čudić

Giulianotti

et al. 2013

Journal of Biological Chemistry

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Background: Structural determinants of ADAM17 substrate specificity are unknown. Results: ADAM17 activity affected by noncatalytic domains and secondary structure of substrates. Conclusion: Noncatalytic domains and substrate conformation are potentially the key structural elements that determine ADAM17 specificity. Significance: Understanding interaction of ADAM17 with its substrates will assist in discovery ADAM isoform-and substratespecific inhibitors.

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“…Indeed, D14 0 isoform lacks the hypervariable region, so the intact disintegrin domain would be more readily available to interact with an integrin molecule. In contrast, three-dimensional data suggest that the disintegrin domain in wild-type ADAM8 would be partially hidden by the hypervariable region (Takeda et al, 2007). These structural differences could explain the higher activity of the D14 0 isoform than the full-length isoform in the fusion of mononuclear precursors.…”

Section: Discussionmentioning

confidence: 93%

Novel alternatively spliced ADAM8 isoforms contribute to the aggressive bone metastatic phenotype of lung cancer

et al. 2010

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ADAMs (a disintegrin and metalloprotease) are transmembrane proteins involved in a variety of physiological processes and tumorigenesis. Recently, ADAM8 has been associated with poor prognosis of lung cancer. However, its contribution to tumorigenesis in the context of lung cancer metastasis remains unknown. Native ADAM8 expression levels were lower in lung cancer cell lines. In contrast, we identified and characterized two novel spliced isoforms encoding truncated proteins, D18a and D14 0 , which were present in several tumor cell lines and not in normal cells. Overexpression of D18a protein resulted in enhanced invasive activity in vitro. ADAM8 and its D14 0 isoform expression levels were markedly increased in lung cancer cells, in conditions mimicking tumor microenvironment. Moreover, addition of supernatants from D14 0 -overexpressing cells resulted in a significant increase in tartrate-resistant acid phosphatase þ cells in osteoclast cultures in vitro. These findings were associated with increased pro-osteoclastogenic cytokines interleukin (IL)-8 and IL-6 protein levels. Furthermore, lung cancer cells overexpressing D14 0 increased prometastatic activity with a high tumor burden and increased osteolysis in a murine model of bone metastasis. Thus, the expression of truncated forms of ADAM8 by the lung cancer cells may result in the specific upregulation of their invasive and osteoclastogenic activities in the bone microenvironment. These findings suggest a novel mechanism of tumor-induced osteolysis in metastatic bone colonization.

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Crystal structure of RVV‐X: An example of evolutionary gain of specificity by ADAM proteinases

Cited by 89 publications

References 21 publications

Cross-domain inhibition of TACE ectodomain

Cross-domain inhibition of TACE ectodomain

Activity of ADAM17 (a Disintegrin and Metalloprotease 17) Is Regulated by Its Noncatalytic Domains and Secondary Structure of its Substrates

Novel alternatively spliced ADAM8 isoforms contribute to the aggressive bone metastatic phenotype of lung cancer

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