ADAMTS proteinases: a multi-domain, multi-functional family with roles in extracellular matrix turnover and arthritis

ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) proteinases are a group of secreted enzymes; many of them have been found to be expressed in cartilage [1]. Functional investigations of these enzymes have largely been limited to a few specific members, particularly ADAMTS-4, which has been implicated in the progression of arthritis [2,3]. The purpose of this review is to summarise the structure, function and regulation of the entire ADAMTS group of proteinases and to emphasise areas of potential relevance with regard to the homeostasis and pathology of connective tissues.ADAMTS proteinases were first described in mice by Kuno and colleagues in 1997 [4] and have subsequently been identified in mammals and Caenorhabditis elegans. They form part of subfamily B (adamalysin subfamily), family M12, in clan MA of the metallopeptidases, as defined in the MEROPS database [5,6] and are structurally and evolutionarily related to the ADAM (a disintegrin and metalloproteinase; also part of the adamalysin subfamily) enzymes and, more distantly, the matrix metalloproteinase (MMP; family M10 in clan MA) enzymes. A comparison of the minimal characteristic domain organisation of these groups of proteinases is shown in Fig. 1.Nineteen distinct human ADAMTS gene products have been identified. A nearest-neighbour dendrogram constructed (using ClustalW 1.7 [7]) from sequence alignments of the entire protein indicates that human ADAMTS proteins can be broadly divided into four subdivisions, which also seem to share structural characteristics and activities (see Fig. 2 and below). A dendrogram constructed from the sequence alignment of the catalytic domains was almost identical, which implies that the catalytic and ancillary domains evolved together (data not shown). The first of the divisions, consisting of ADAMTS-1, -4, -5, -8, -9, -15 and -20, subdivides into two further groups, one composed of ADAMTS-9 and -20 and the other of ADAMTS-1, -4, -5, -8 and -15. A seco