Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-α

Tumour-necrosis factor-α (TNF-α) is a cytokine that contributes to a variety of inflammatory disease states1. The protein exists as a membrane-bound precursor2,3 of relative molecular mass 26K which can be processed by a TNF-α-converting enzyme (TACE), to generate secreted 17K mature TNF-α. We have purified TACE and cloned its complementary DNA. TACE is a membrane-bound disintegrin metalloproteinase. Structural comparisons with other disintegrin-containing enzymes indicate that TACE is unique, with noteable sequence identity to MADM4, an enzyme implicated in myelin degradation, and to KUZ5, a Drosophila homologue of MADM important for neuronal development. The expression of recombinant TACE (rTACE) results in the production of functional enzyme that correctly processes precursor TNF-α to the mature form. The rTACE provides a readily available source of enzyme to help in the search for new anti-inflammatory agents that target the final processing stage of TNF-α production.