CLONING OF A DISINTEGRIN METALLOPROTEINASE THAT PROCESSES PRECURSOR TUMOR-NECROSIS-FACTOR-ALPHA

Tumour-necrosis factor-alpha (TNF-alpha) is a cytokine that contribute s to a variety of inflammatory disease states(1). The protein exists a s a membrane-bound precursor(2,3) of relative molecular mass 26K which can be processed by a TNF-alpha-converting enzyme (TACE), to generate secreted 17K mature TNF-alpha. We have purified TACE and cloned its c omplementary DNA. TACE is a membrane-bound disintegrin metalloproteina se. Structural comparisons with other disintegrin-containing enzymes i ndicate that TACE is unique, with noteable sequence identity to MADM(4 ), an enzyme implicated in myelin degradation, and to KUZ(5), a Drosop hila homologue of MADM important for neuronal development. The express ion of recombinant TACE (rTACE) results in the production of functiona l enzyme that correctly processes precursor TNF-alpha to the mature fo rm. The rTACE provides a readily available source of enzyme to help in the search for new anti-inflammatory agents that target the final pro cessing stage of TNF-alpha production.