title: The C-terminal domains of TACE weaken the inhibitory action of N-TIMP-3.
abstract: Tumor necrosis factor-alpha converting enzyme (TACE) is an ADAM (a disintegrin and metalloproteinases) that comprises an active catalytic domain and several C-terminal domains. We compare the binding affinity and association rate constants of the N-terminal domain form of wild-type tissue inhibitor of metalloproteinase (TIMP-3; N-TIMP-3) and its mutants against full-length recombinant TACE and the truncated form of its catalytic domain. We show that the C-terminal domains of TACE substantially weaken the inhibitory action of N-TIMP-3. Further probing with hydroxamate inhibitors indicates that both forms of TACE have similar active site configurations. Our findings highlight the potential role of the C-terminal domains of ADAM proteinases in influencing TIMP interactions.
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK. meng.lee@uea.ac.uk
authors.forename: Meng-Huee
authors.initials: MH
authors.lastname: Lee
authors.forename: Vandana
authors.initials: V
authors.lastname: Verma
authors.forename: Klaus
authors.initials: K
authors.lastname: Maskos
authors.forename: J David
authors.initials: JD
authors.lastname: Becherer
authors.forename: Vera
authors.initials: V
authors.lastname: Knäuper
authors.forename: Philippa
authors.initials: P
authors.lastname: Dodds
authors.forename: Augustin
authors.initials: A
authors.lastname: Amour
authors.forename: Gillian
authors.initials: G
authors.lastname: Murphy
mesh_terms: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D019943:Amino Acid Substitution; D020134:Catalytic Domain / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000494:pharmacology; D007700:Kinetics; D007930:Leucine / Q000235:genetics; D008666:Metalloendopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D012694:Serine / Q000235:genetics; D013912:Threonine / Q000235:genetics; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D011994:Recombinant Proteins; D019717:Tissue Inhibitor of Metalloproteinase-3; D013912:Threonine; D012694:Serine; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; D007930:Leucine