The C-terminal domains of TACE weaken the inhibitory action of N-TIMP-3

FEBS Lett. 2002 Jun 5;520(1-3):102-6. doi: 10.1016/s0014-5793(02)02776-x.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins
  • ADAM17 Protein
  • Amino Acid Substitution
  • Catalytic Domain / genetics
  • Enzyme Inhibitors / pharmacology
  • Hydroxamic Acids / pharmacology
  • Kinetics
  • Leucine / genetics
  • Metalloendopeptidases / chemistry
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / metabolism*
  • Mutation
  • Recombinant Proteins / drug effects
  • Recombinant Proteins / metabolism
  • Serine / genetics
  • Threonine / genetics
  • Tissue Inhibitor of Metalloproteinase-3 / chemistry
  • Tissue Inhibitor of Metalloproteinase-3 / genetics
  • Tissue Inhibitor of Metalloproteinase-3 / metabolism*

Substances

  • Enzyme Inhibitors
  • Hydroxamic Acids
  • Recombinant Proteins
  • Tissue Inhibitor of Metalloproteinase-3
  • Threonine
  • Serine
  • ADAM Proteins
  • Metalloendopeptidases
  • ADAM17 Protein
  • Leucine