ADAMTS proteins in human disorders

ADAMTS proteins are a superfamily of 26 secreted molecules comprising two related, but distinct families. ADAMTS proteases are zinc metalloendopeptidases, most of whose substrates are extracellular matrix (ECM) components, whereas ADAMTS-like proteins lack a metalloprotease domain, reside in the ECM...

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Bibliographic Details
Published in:Matrix biology 2018-10, Vol.71-72, p.225-239
Main Authors: Mead, Timothy J., Apte, Suneel S.
Format: Article
Language:English
Subjects:
Aggrecan
Arteriosclerosis
Atherosclerosis
Autoantibodies
Cartilage diseases
Congenital defects
Coronary artery
Evolutionary conservation
Extracellular matrix
Genetic engineering
Genome-wide association studies
Genome-wide association studies (GWAS)
Genomes
Genotype & phenotype
Heart diseases
Mammals
Medical disorders
Metalloprotease
Metalloproteinase
Mutation
Osteoarthritis
Pathogenesis
Phenotypes
Protease
Proteins
Purpura
Thrombocytopenic purpura
Thrombotic thrombocytopenic purpura
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Summary:ADAMTS proteins are a superfamily of 26 secreted molecules comprising two related, but distinct families. ADAMTS proteases are zinc metalloendopeptidases, most of whose substrates are extracellular matrix (ECM) components, whereas ADAMTS-like proteins lack a metalloprotease domain, reside in the ECM and have regulatory roles vis-à-vis ECM assembly and/or ADAMTS activity. Evolutionary conservation and expansion of ADAMTS proteins in mammals is suggestive of crucial embryologic or physiological roles in humans. Indeed, Mendelian disorders or birth defects resulting from naturally occurring ADAMTS2, ADAMTS3, ADAMTS10, ADAMTS13, ADAMTS17, ADAMTS20, ADAMTSL2 and ADAMTSL4 mutations as well as numerous phenotypes identified in genetically engineered mice have revealed ADAMTS participation in major biological pathways. Important roles have been identified in a few acquired conditions. ADAMTS5 is unequivocally implicated in pathogenesis of osteoarthritis via degradation of aggrecan, a major structural proteoglycan in cartilage. ADAMTS7 is strongly associated with coronary artery disease and promotes atherosclerosis. Autoantibodies to ADAMTS13 lead to a platelet coagulopathy, thrombotic thrombocytopenic purpura, which is similar to that resulting from ADAMTS13 mutations. ADAMTS proteins have numerous potential connections to other human disorders that were identified by genome-wide association studies. Here, we review inherited and acquired human disorders in which ADAMTS proteins participate, and discuss progress and prospects in therapeutics. •The ADAMTS superfamily comprises extracellular matrix modifying proteases and non-structural proteins.•ADAMTS gene mutations lead to diverse inherited disorders.•Inhibition of ADAMTS protease activity is a translational possibility in treatment of osteoarthritis and atherosclerosis.•Recombinant ADAMTS13 is under development for thrombotic thrombocytopenic purpura.
ISSN:0945-053X
1569-1802
DOI:10.1016/j.matbio.2018.06.002