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 proTNFa, 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.
Journal
Proceedings of the National Academy of Sciences