ADAMTS evolution and structure

Members of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family are known to influence development, angiogenesis, coagulation and progression of arthritis. As proteinases their substrates include the von Willebrand factor precursor and extracellular matrix components such as procollagen, hyalectans (hyaluronan-binding proteoglycans including aggrecan), decorin, fibromodulin and cartilage oligomeric matrix protein. ADAMTS levels and activities are regulated at multiple levels through the control of gene expression, mRNA splicing, protein processing and inhibition by TIMP (tissue inhibitor of metalloproteinases). A recent screen of human cartilage has shown that multiple members of the ADAMTS family may be important in connective tissue homeostasis and pathology. Introduction 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 evolution and structure 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 second, well-defined, subgroup contains ADAMTS-2, -3 and -14. ADAMTS-13 stands alone, and the remaining ADAMTS members form a loosely defined subgroup within which members are further divided into four pairs (ADAMTS-19 and -17, ADAMTS-18 and -16, ADAMTS-12 and -7, and ADAMTS-10 and -6) sharing structural features. A detailed study of the phylogenetic relationship of the ADAMTS family members has recently been published [8]. ADAMTS domain structure The signal sequence of ADAMTS proteins is followed by a pro-region of varying length, but which is unusually short in ADAMTS-13. The pro-domain of all ADAMTS proteinases contains at least one furin cleavage consensus motif; it is therefore generally believed that the zymogen forms of Review ADAMTS proteinases: a multi-domain, multi-functional family with roles in extracellular matrix turnover and arthritis Gavin C Jones and Graham P Riley Rheumatology Research Unit, Addenbrooke’s Hospital, Cambridge, UK Corresponding author: Gavin C Jones, [email protected] Published: 21 June 2005 Arthritis Research & Therapy 2005, 7:160-169 (DOI 10.1186/ar1783) This article is online at http://arthritis-research.com/content/7/4/160 © 2005 BioMed Central Ltd