A disintegrin-like and metalloprotease (reprolysin-type) with thrombospondin type 1 motif (ADAMTS) superfamily: functions and mechanisms

Abstract

Together with seven ADAMTS-like proteins, the 19 mammalian ADAMTS proteases constitute a superfamily. ADAMTS proteases are secreted zinc metalloproteases whose hallmark is an ancillary domain containing one or more thrombospondin type 1 repeats. ADAMTS-like proteins resemble ADAMTS ancillary domains and lack proteolytic activity. Vertebrate expansion of the superfamily reflects emergence of new substrates, duplication of proteolytic activities in new contexts, and cooperative functions of the duplicated genes. ADAMTS proteases are involved in maturation of procollagen and von Willebrand factor, as well as in extracellular matrix proteolysis relating to morphogenesis, angiogenesis, ovulation, cancer, and arthritis. New insights into ADAMTS mechanisms indicate significant regulatory roles for ADAMTS ancillary domains, propeptide processing, and glycosylation. ADAMTS-like proteins appear to have regulatory roles in the extracellular matrix.

FIGURE 1.

Mammalian ADAMTS proteases. The domain backbone shared by each ADAMTS protease is shown at the top. The unique structure of each ADAMTS protease C-terminal to the backbone is indicated on the right, and the key to these modules is located on the left. Some clades are named according to structural or functional characteristics that best define them; clades without a known function or a defining characteristic are not named. The proteoglycanases constitute a superclade comprising ADAMTS proteases with different domain structure. The figure is based on reference sequences obtained from GenBank^TM. PLAC, protease and lacunin module.

FIGURE 2.

Mammalian ADAMTSL proteins. The domain structure of each ADAMTSL is shown according to the key at the bottom. The two forms of ADAMTSL1 shown are splice variants, and the long form composes a clade with ADAMTSL3. ADAMTSL4 and ADAMTSL6 compose a distinct clade in which TSR1 is split by an insertion. The figure is based on reference sequences obtained from GenBank^TM. aa, amino acids. PLAC, protease and lacunin module.