Crystal Structures of Human ADAMTS-1 Reveal a Conserved Catalytic Domain and a Disintegrin-like Domain with a Fold Homologous to Cysteine-Rich Domains

• Published in: Journal of molecular biology Vol. 373; no. 4; pp. 891 - 902
• Main Authors: Gerhardt, Stefan, Hassall, Giles, Hawtin, Paul, McCall, Eileen, Flavell, Liz, Minshull, Claire, Hargreaves, David, Ting, Attilla, Pauptit, Richard A., Parker, Andrew E., Abbott, W. Mark
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 02.11.2007
• Subjects: ADAM Proteins - chemistry; ADAM Proteins - genetics; ADAM Proteins - metabolism; ADAMTS-1; 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; metalloproteinase; Models, Molecular; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary; X-ray structure; ADAM; MMP; ADAMTS-1; metalloproteinase; ADAMTS; S-SAD; X-ray structure
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2007.07.047

The ADAMTS ( a disintegrin-like and metalloproteinase domain with thrombo spondin 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.