Functional analysis of the domain structure of tumor necrosis factor-α converting enzyme

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Abstract

Many membrane-bound proteins, including cytokines, receptors, and growth factors, are proteolytically cleaved to release a soluble form of their extracellular domain. The tumor necrosis factor (TNF)-α converting enzyme (TACE/ADAM-17) is a transmembrane metalloproteinase responsible for the proteolytic release or 'shedding' of several cell-surface proteins, including TNF and p75 TNFR. We established a TACE-reconstitution system using TACE- deficient cells co-transfected with TACE and substrate cDNAs to study TACE function and regulation. Using the TACE-reconstitution system, we identified two additional substrates of TACE, interleukin (IL)-1R-II and p55 TNFR. Using truncations and chimeric constructs of TACE and another ADAM family member, ADAM-10, we studied the function of the different domains of TACE in three shedding activities. We found that TACE must be expressed with its membrane- anchoring domain for phorbol ester-stimulated shedding of TNF, p75 TNFR, and IL-1R-II, but that the cytoplasmic domain is not required for the shedding of these substrates. The catalytic domain of ADAM-10 could not be functionally substituted for that of TACE. IL-1R-II shedding required the cysteine-rich domain of TACE as well as the catalytic domain, whereas TNF and p75 TNFR shedding required only the tethered TACE catalytic domain.

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Reddy, P., Slack, J. L., Davis, R., Cerretti, D. P., Kozlosky, C. J., Blanton, R. A., … Black, R. A. (2000). Functional analysis of the domain structure of tumor necrosis factor-α converting enzyme. Journal of Biological Chemistry, 275(19), 14608–14614. https://doi.org/10.1074/jbc.275.19.14608

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