TACE is a membrane-bound metalloproteinase localized on the outer surface of virtually every cell of the human body. This multidomain zinc enzyme has recently been identified to cleave the membrane-bound precursor of the tumor necrosis factor-
A research group of the Department for Structural Research at the Max Planck Institute of Biochemistry in Martinsried c/o Munich, Germany, in cooperation with scientists from Immunex/Seattle, Wyeth-Ayerst/New York, and the Max Planck Research Unit for Proteindynamics in Hamburg solved the crystal structure of the catalytic domain of human necrosis factor- a -converting enzyme (TACE).
The Max Planck team (Dr. Klaus Maskos, Carlos Fernandez-Catalan, Marianne Braun and Prof. Wolfram Bode) was able to crystallize the recombinant catalytic domain of TACE cloned and purified by the Immunex team (headed by Dr. Roy Black), and to solve its structure using synchrotron radiation and multiple wavelengths diffraction (MAD) methods at the DESY/Hamburg (Dr. Hans Bartunik).
The results of this study have now been published by Maskos et.al. in the Proceedings of the National Academy of Sciences, USA (1998), 95 (7), 3408-3412. This structure reveals some topological similarities with the catalytic domain of a snake venom metalloproteinase previously elucidated by the same Martinsried group, with a number of large polypeptide insertion loops generating unique features at the molecular surface, however. The active site region of the TACE molecule also shares properties with the matrix metalloproteinases (to which collagenases, gelatinases and stromelysins belong), but differs considerably in its substrate binding features. The structure of the human necrosis factor- a -converting enzyme helps to explain the specific capability of TACE to cleave proTNF a , but also provides the structural basis for the rational design of specific inhibitors, which could selectively impair the catalytic action of TACE.
The TACE structure thus opens a new approach toward the structure-based design of specific synthetic TACE inhibitors. Such tailored inhibitors could act as effective therapeutic agents against arthritic lesions and might increase the rate of survival in various endotoxin-induced septic shock syndromes.
TACE is a membrane-bound metalloproteinase localized on the outer surface of virtually every cell of the human body. This multidomain zinc enzyme has recently been identified to cleave the membrane-bound precursor of the tumor necrosis factor-
Proceedings of the National Academy of Sciences