The ADAMTS metalloproteinases

Abstract

The ADAMTSs (a disintegrin and metalloproteinase with thrombospondin motifs) are a group of proteases that are found both in mammals and invertebrates. Since the prototype ADAMTS-1 was first described in 1997, there has been a rapidly expanding body of literature describing this gene family and the proteins they encode. The complete human family has 19 ADAMTS genes, together with three members of a newly identified subgroup, the ADAMTSL (ADAMTS-like) proteins, which have several domains in common with the ADAMTSs. The ADAMTSs are extracellular, multidomain enzymes whose known functions include: (i) collagen processing as procollagen N-proteinase; (ii) cleavage of the matrix proteoglycans aggrecan, versican and brevican; (iii) inhibition of angiogenesis; and (iv) blood coagulation homoeostasis as the von Willebrand factor cleaving protease. Roles in organogenesis, inflammation and fertility are also apparent. Recently, some ADAMTS genes have been found to show altered expression in arthritis and various cancers. This review highlights progress in understanding the structural organization and functional roles of the ADAMTSs in normal and pathological conditions.

Figure 1. Domain structure of the ADAMTS proteins

In the case of proteins with varying isoforms, only the longest isoform is represented here. The thrombospondin type 1 domains are highlighted by the oval shapes.

Figure 2. Diagram to show the approximate C-terminal cleavage points (indicated by arrowheads) of ADAMTS-1, ADAMTS-4 and ADAMTS-12

ADAMTS-8 and ADAMTS-9 are also reported to undergo C-terminal cleavage, but details are not known.

Figure 3. A diagrammatic representation of aggrecan and its known cleavage sites

Aggrecan has two cleavage sites situated within the G1/G2 IGD domain. The Asn³⁴¹–Phe³⁴² is the main MMP cleavage site, whereas the Glu³⁷³–Ala³⁷⁴ is cleaved by aggrecanases. There are also four cleavage sites within the chondroitin sulphate-rich region of aggrecan which at least ADAMTS4 and ADAMTS5 are known to cleave. The black arrows on the diagram represent the site at which cleavage takes place.