Abstract
Secreted a disintegrin-like and metalloprotease with thrombospondin type 1 motif (ADAMTS) proteases play crucial roles in tissue development and homeostasis. The biological and pathological functions of ADAMTS proteases are determined broadly by their respective substrates and their interactions with proteins in the pericellular and extracellular matrix. For some ADAMTS proteases, substrates have been identified and substrate cleavage has been implicated in tissue development and in disease. For other ADAMTS proteases, substrates were discovered in vitro, but the role of these proteases and the consequences of substrate cleavage in vivo remains to be established. Mutations in ADAMTS10 and ADAMTS17 cause Weill–Marchesani syndrome (WMS), a congenital syndromic disorder that affects the musculoskeletal system (short stature, pseudomuscular build, tight skin), the eyes (lens dislocation), and the heart (heart valve abnormalities). WMS can also be caused by mutations in fibrillin-1 (FBN1), which suggests that ADAMTS10 and ADAMTS17 cooperate with fibrillin-1 in a common biological pathway during tissue development and homeostasis. Here, we compare and contrast the biochemical properties of ADAMTS10 and ADAMTS17 and we summarize recent findings indicating potential biological functions in connection with fibrillin microfibrils. We also compare ADAMTS10 and ADAMTS17 with their respective sister proteases, ADAMTS6 and ADAMTS19; both were recently linked to human disorders distinct from WMS. Finally, we propose a model for the interactions and roles of these four ADAMTS proteases in the extracellular matrix.
Highlights
The family of a disintegrin-like and metalloprotease with thrombospondin type 1 motif (ADAMTS) comprises 19 secreted metalloproteases, which are primarily involved in the formation, remodeling, and/or degradation of components of the extracellular matrix (ECM) [1]
All of the ADAMTS proteases share a similar domain organization with a conserved N-terminal protease domain and a variable C-terminal ancillary domain, which is implicated in substrate recognition and ECM binding (Figure 1a) [2,3,4]
The conserved ADAMTS protease domain consists of a signal peptide to target ADAMTS proteases for secretion, a propeptide that is typically removed by furin/PACE proprotein convertases to activate ADAMTS proteases, the catalytic metalloproteinase domain itself, and a disintegrin-like domain
Summary
The family of a disintegrin-like and metalloprotease with thrombospondin type 1 motif (ADAMTS) comprises 19 secreted metalloproteases, which are primarily involved in the formation, remodeling, and/or degradation of components of the extracellular matrix (ECM) [1]. The four ADAMTS proteases show differences in the number and localization of predicted sites for posttranslational modifications, such as N-glycosylation (http://www.cbs.dtu.dk/services/NetNGlyc/), O-fucosylation, and furin processing which could specify individual substrates, define protein-protein interactions, Biomolecules 2020, 10, 596 modifications. The four ADAMTS proteases show differences in the number and localization of predicted sites for posttranslational modifications, such as N-glycosylation (http://www.cbs.dtu.dk/services/NetNGlyc/), O-fucosylation, and furin processing which could specify individual substrates, define protein-protein interactions, or govern autocatalytic properties that collectively distinguish these four ADAMTS proteases from each other. In addition to alternative splicing, ADAMTS6, 10, 17, and 19 show differences in the number and location of predicted and experimentally verified posttranslational modifications, such as furin/PACE-processing, autocatalysis, N-glycosylation, or O-fucosylation. Aortic valve dysfunction in ~40% of knockout mice n.d. n.d
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