Crystal structures of human ADAMTS-1 reveal a conserved catalytic domain and a disintegrin-like domain with a fold homologous to cysteine-rich domains

J Mol Biol. 2007 Nov 2;373(4):891-902. doi: 10.1016/j.jmb.2007.07.047. Epub 2007 Aug 2.

Abstract

The ADAMTS (a disintegrin-like and metalloproteinase domain with thrombospondin type I motifs) family of proteases plays a role in pathological conditions including arthritis, cancer, thrombotic thrombocytopenic purpura and the Ehlers-Danlos type VIIC and Weill-Marchesani genetic syndromes. Here, we report the first crystal structures for a member of the ADAMTS family, ADAMTS-1. Originally cloned as an inflammation-associated gene, ADAMTS-1 has been shown to be involved in tissue remodelling, wound healing and angiogenesis. The crystal structures contain catalytic and disintegrin-like domains, both in the inhibitor-free form and in complex with the inhibitor marimastat. The overall fold of the catalytic domain is similar to related zinc metalloproteinases such as matrix metalloproteinases and ADAMs (a disintegrin and metalloproteinases). The active site contains the expected organisation of residues to coordinate zinc but has a much larger S1' selectivity pocket than ADAM33. The structure also unexpectedly reveals a double calcium-binding site. Also surprisingly, the previously named disintegrin-like domain showed no structural homology to the disintegrin domains of other metalloproteinases such as ADAM10 but is instead very similar in structure to the cysteine-rich domains of other metalloproteinases. Thus, this study suggests that the D (for disintegrin-like) in the nomenclature of ADAMTS enzymes is likely to be a misnomer. The ADAMTS-1 cysteine-rich domain stacks against the active site, suggesting a possible regulatory role.

MeSH terms

  • ADAM Proteins / chemistry*
  • ADAM Proteins / genetics
  • ADAM Proteins / metabolism
  • ADAMTS1 Protein
  • Binding Sites
  • Calcium / metabolism
  • Catalytic Domain
  • Crystallography, X-Ray / methods
  • Disintegrins / chemistry*
  • Disintegrins / genetics
  • Disintegrins / metabolism
  • Humans
  • Metalloendopeptidases / chemistry
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / metabolism
  • Models, Molecular
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary

Substances

  • Disintegrins
  • ADAM Proteins
  • ADAMTS1 Protein
  • ADAMTS1 protein, human
  • Metalloendopeptidases
  • Calcium

Associated data

  • PDB/2JIH
  • PDB/2V4B