Article (Scientific journals)
Proteomic discovery of substrates of the cardiovascular protease ADAMTS7.
Colige, Alain; Monseur, Christine; Crawley, JTB et al.
2019In Journal of Biological Chemistry
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Abstract :
[en] The protease ADAMTS7 functions in the extracellular matrix (ECM) of the cardiovascular system. However, its physiological substrate specificity and mechanism of regulation remain to be explored. To address this, we conducted an unbiased substrate analysis using terminal amine isotopic labeling of substrates (TAILS). The analysis identified candidate substrates of ADAMTS7 in the human fibroblast secretome, including proteins with a wide range of functions, such as collagenous and non-collagenous ECM proteins, growth factors, proteases, and cell-surface receptors. It also suggested that autolysis occurs at Glu729-Val730 and Glu732-Ala733 in the ADAMTS7 spacer domain, which was corroborated by N-terminal sequencing and western blotting. Importantly, TAILS also identified proteolysis of the latent TGF-β-binding proteins 3 and 4 (LTBP3/4) at a Glu-Val and Glu-Ala site, respectively. Using purified enzyme and substrate, we confirmed ADAMTS7-catalyzed proteolysis of recombinant LTBP4. Moreover, we identified multiple additional scissile bonds in an N-terminal linker region of LTBP4 that connects fibulin-5/tropoelastin and fibrillin-1-binding regions, which have an important role in elastogenesis. ADAMTS7-mediated cleavage of LTBP4 was efficiently inhibited by the metalloprotease inhibitor TIMP-4, but not by TIMP-1 and less efficiently by TIMP-2 and TIMP-3. As TIMP-4 expression is prevalent in cardiovascular tissues, we propose that TIMP-4 represents the primary endogenous ADAMTS7 inhibitor. In summary, our findings reveal LTBP4 as an ADAMTS7 substrate, whose cleavage may potentially impact elastogenesis in the cardiovascular system. We also identify TIMP-4 as a likely physiological ADAMTS7 inhibitor.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Colige, Alain ;  Université de Liège - ULiège > GIGA-Cancer > Laboratory of Connective Tissues Biology
Monseur, Christine ;  Université de Liège - ULiège > GIGA > Laboratory of Connective Tissue Biology
Crawley, JTB;  Imperial College London, United Kingdom. > Haematology
Santamaria, S;  Imperial College London, United Kingdom.
de Groot, Rens;  Imperial College London, United Kingdom. > Centre for Haematology
Language :
Title :
Proteomic discovery of substrates of the cardiovascular protease ADAMTS7.
Publication date :
29 March 2019
Journal title :
Journal of Biological Chemistry
Publisher :
American Society for Biochemistry and Molecular Biology, United States - Maryland
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 26 April 2019


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