Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha.
Tumour-necrosis factor-alpha (TNF-alpha) is a cytokine that contributes to a variety of inflammatory disease states. The protein exists as a membrane-bound precursor 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 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 MADM, an enzyme implicated in myelin degradation, and to KUZ, 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-alpha 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-alpha production.
Moss
M L
ML
Department of Molecular Biochemistry, Glaxo Wellcome Research and Development Inc., Research Triangle Park, North Carolina 27709, USA.
Jin
S L
SL
Milla
M E
ME
Bickett
D M
DM
Burkhart
W
W
Carter
H L
HL
Chen
W J
WJ
Clay
W C
WC
Didsbury
J R
JR
Hassler
D
D
Hoffman
C R
CR
Kost
T A
TA
Lambert
M H
MH
Leesnitzer
M A
MA
McCauley
P
P
McGeehan
G
G
Mitchell
J
J
Moyer
M
M
Pahel
G
G
Rocque
W
W
Overton
L K
LK
Schoenen
F
F
Seaton
T
T
Su
J L
JL
Becherer
J D
JD
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D003001:Cloning, Molecular; D017124:Conserved Sequence; D019483:Disintegrins / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D008666:Metalloendopeptidases / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism; D008969:Molecular Sequence Data; D011498:Protein Precursors / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D019483:Disintegrins; D008565:Membrane Proteins; D011498:Protein Precursors; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human