Proteomic discovery of substrates of the cardiovascular protease ADAMTS7.

Published on May 17, 2019in Journal of Biological Chemistry4.238
· DOI :10.1074/JBC.RA119.007492
Alain Colige12
Estimated H-index: 12
(University of Liège),
Alain Colige50
Estimated H-index: 50
(University of Liège)
+ 2 AuthorsRens de Groot9
Estimated H-index: 9
(Imperial College London)
Sources
Abstract
: 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 noncollagenous extracellular matrix proteins, growth factors, proteases, and cell-surface receptors. It also suggested that autolysis occurs at Glu-729-Val-730 and Glu-732-Ala-733 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.
📖 Papers frequently viewed together
70 Citations
263 Citations
142 Citations
References53
Newest
#1Rens de Groot (Imperial College London)H-Index: 9
: ADAMTS7 is a secreted protease that is predominantly expressed in tissues of the cardiovascular system and tendon. Although recent evidence suggests that it may play a role in the etiology of coronary artery disease, its physiological function and substrates are unknown. The enzyme undergoes extensive posttranslational modifications, including chondroitin sulfate attachment, N and O-linked glycosylation, and a two-step activation process. For the benefit of scientists who study the function of...
1 CitationsSource
#1Lauren W. Wang (Cleveland Clinic)H-Index: 19
#2Wendy E. Kutz (Cleveland Clinic)H-Index: 3
Last. Suneel S. Apte (Cleveland Clinic)H-Index: 72
view all 8 authors...
Abstract Mutations in the secreted metalloproteinase ADAMTS10 cause recessive Weill-Marchesani syndrome (WMS), comprising ectopia lentis, short stature, brachydactyly, thick skin and cardiac valve anomalies. Dominant WMS caused by FBN1 mutations is clinically similar and affects fibrillin-1 microfibrils, which are a major component of the ocular zonule. ADAMTS10 was previously shown to enhance fibrillin-1 assembly in vitro. Here, Adamts10 null mice were analyzed to determine the impact of ADAMTS...
19 CitationsSource
#1E.J. Mularczyk (University of Manchester)H-Index: 1
#2Mukti Singh (University of Manchester)H-Index: 4
Last. Clair Baldock (University of Manchester)H-Index: 33
view all 13 authors...
: Fibrillin microfibrils are extracellular matrix assemblies that form the template for elastic fibres, endow blood vessels, skin and other elastic tissues with extensible properties. They also regulate the bioavailability of potent growth factors of the TGF-β superfamily. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)10 is an essential factor in fibrillin microfibril function. Mutations in fibrillin-1 or ADAMTS10 cause Weill-Marchesani syndrome (WMS) characterized by sh...
16 CitationsSource
#1Timothy J. Mead (Cleveland Clinic Lerner Research Institute)H-Index: 10
#2Daniel R. McCulloch (Cleveland Clinic Lerner Research Institute)H-Index: 1
Last. Suneel S. Apte (Cleveland Clinic Lerner Research Institute)H-Index: 72
view all 7 authors...
: Heterotopic ossification (HO) is a significant clinical problem with incompletely resolved mechanisms. Here, the secreted metalloproteinases ADAMTS7 and ADAMTS12 are shown to comprise a unique proteoglycan class that protects against a tendency toward HO in mouse hindlimb tendons, menisci, and ligaments. Adamts7 and Adamts12 mRNAs were sparsely expressed in murine forelimbs but strongly coexpressed in hindlimb tendons, skeletal muscle, ligaments, and meniscal fibrocartilage. Adamts7-/- Adamts1...
16 CitationsSource
#1Dongchuan Guo (University of Texas Health Science Center at Houston)H-Index: 39
#2Ellen S. Regalado (University of Texas Health Science Center at Houston)H-Index: 28
Last. Dianna M. Milewicz (University of Texas Health Science Center at Houston)H-Index: 84
view all 17 authors...
The major diseases affecting the thoracic aorta are aneurysms and acute dissections, and pathogenic variants in 11 genes are confirmed to lead to heritable thoracic aortic disease. However, many families in which multiple members have thoracic aortic disease do not have alterations in the known aortopathy genes. Genes highly expressed in the aorta were assessed for rare variants in exome sequencing data from such families, and compound rare heterozygous variants (p.Pro45Argfs ∗ 25 and p.Glu750 ∗...
22 CitationsSource
#1Daniel B. Rifkin (NYU: New York University)H-Index: 116
#2William J. Rifkin (NYU: New York University)H-Index: 12
Last. Lior Zilberberg (NYU: New York University)H-Index: 15
view all 3 authors...
The latent transforming growth factor (TGF) β binding proteins (LTBP) are crucial mediators of TGFβ function, as they control growth factor secretion, matrix deposition, presentation and activation. Deficiencies in specific LTBP isoforms yield discrete phenotypes representing defects in bone, lung and cardiovascular development mediated by loss of TGFβ signaling. Additional phenotypes represent loss of unique TGFβ-independent features of LTBP effects on elastogenesis and microfibril assembly. Th...
31 CitationsSource
#1Lukas Zimmermann (MPG: Max Planck Society)H-Index: 1
#2Andrew Stephens (MPG: Max Planck Society)H-Index: 1
Last. Vikram Alva (MPG: Max Planck Society)H-Index: 18
view all 10 authors...
Abstract The MPI Bioinformatics Toolkit ( https://toolkit.tuebingen.mpg.de ) is a free, one-stop web service for protein bioinformatic analysis. It currently offers 34 interconnected external and in-house tools, whose functionality covers sequence similarity searching, alignment construction, detection of sequence features, structure prediction, and sequence classification. This breadth has made the Toolkit an important resource for experimental biology and for teaching bioinformatic inquiry. Re...
874 CitationsSource
#1Sophia Doll (UCPH: University of Copenhagen)H-Index: 16
#2Martina Dreßen (TUM: Technische Universität München)H-Index: 9
Last. Matthias Mann (UCPH: University of Copenhagen)H-Index: 240
view all 12 authors...
The heart is a central human organ and its diseases are the leading cause of death worldwide, but an in-depth knowledge of the identity and quantity of its constituent proteins is still lacking. Here, we determine the healthy human heart proteome by measuring 16 anatomical regions and three major cardiac cell types by high-resolution mass spectrometry-based proteomics. From low microgram sample amounts, we quantify over 10,700 proteins in this high dynamic range tissue. We combine copy numbers p...
102 CitationsSource
#1Eva Bengtsson (Lund University)H-Index: 24
#2Karin Hultman (Lund University)H-Index: 11
Last. Isabel Gonçalves (Lund University)H-Index: 26
view all 10 authors...
Several large-scale genome-wide association studies have identified single-nucleotide polymorphisms in the genomic region of A Disintegrin And Metalloproteinase with ThromboSpondin type 1 repeats (ADAMTS)-7 and associations to coronary artery disease. Experimental studies have provided evidence for a functional role of ADAMTS-7 in both injury-induced vascular neointima formation and development of atherosclerotic lesions. However, whether ADAMTS-7 is associated with a specific plaque phenotype i...
14 CitationsSource
#1Dirk Hubmacher (Cleveland Clinic Lerner Research Institute)H-Index: 19
#2Michael Schneider (SBU: Stony Brook University)H-Index: 79
Last. Suneel S. Apte (Cleveland Clinic Lerner Research Institute)H-Index: 1
view all 8 authors...
Unusual life cycle and impact on microfibril assembly of ADAMTS17, a secreted metalloprotease mutated in genetic eye disease
34 CitationsSource
Cited By7
Newest
#1Keron W. J. Rose (ISMMS: Icahn School of Medicine at Mount Sinai)
#2Nandaraj Taye (ISMMS: Icahn School of Medicine at Mount Sinai)H-Index: 3
Last. Dirk Hubmacher (ISMMS: Icahn School of Medicine at Mount Sinai)H-Index: 19
view all 0 authors...
A disintegrin and metalloprotease with thrombospondin type I motifs (ADAMTS) proteases are secreted metalloproteinases that play key roles in the formation, homeostasis and remodeling of the extracellular matrix (ECM). The substrate spectrum of ADAMTS proteases can range from individual ECM proteins to entire families of ECM proteins, such as the hyalectans. ADAMTS-mediated substrate cleavage is required for the formation, remodeling and physiological adaptation of the ECM to the needs of indivi...
Source
#1Taiji MizoguchiH-Index: 2
#2Bryan T. MacDonald (Broad Institute)H-Index: 25
Last. Virendar K. Kaushik (Broad Institute)H-Index: 8
view all 0 authors...
Rationale: Despite contemporary therapy, coronary artery disease (CAD) remains a leading cause of mortality. Genetic variants at ADAMTS7 have been associated with CAD and the loss of ADAMTS7 is protective for atherosclerosis. ADAMTS7 (a disintegrin and metalloproteinase with thrombospondin motifs 7) is a secreted metalloproteinase and complex proteoglycan, yet the mechanism linking ADAMTS7 to CAD risk remains unresolved. Objective: To investigate the role of ADAMTS7 catalytic function in vascula...
Source
#1Chi-Ting Su (NTU: National Taiwan University)
#2Zsolt Urban (University of Pittsburgh)H-Index: 35
Latent transforming growth factor β (TGFβ)-binding protein (LTBP) 4, a member of the LTBP family, shows structural homology with fibrillins. Both these protein types are characterized by calcium-binding epidermal growth factor-like repeats interspersed with 8-cysteine domains. Based on its domain composition and distribution, LTBP4 is thought to adopt an extended structure, facilitating the linear deposition of tropoelastin onto microfibrils. In humans, mutations in LTBP4 result in autosomal rec...
Source
#1Nathalie Théret (University of Rennes)H-Index: 34
#2Fidaa Bouezzeddine (Lebanese University)
Last. Vincent Legagneux (University of Rennes)H-Index: 18
view all 5 authors...
The tumor microenvironment plays a major role in tumor growth, invasion and resistance to chemotherapy, however understanding how all actors from microenvironment interact together remains a complex issue. The tumor microenvironment is classically represented as three closely connected components including the stromal cells such as immune cells, fibroblasts, adipocytes and endothelial cells, the extracellular matrix (ECM) and the cytokine/growth factors. Within this space, proteins of the adamal...
Source
#1Nikos K. Karamanos (FORTH: Foundation for Research & Technology – Hellas)H-Index: 61
#2Achilleas D. Theocharis (University of Patras)H-Index: 43
Last. Maurizio Onisto (UNIPD: University of Padua)H-Index: 28
view all 17 authors...
Extracellular matrix (ECM) is a dynamic 3-dimensional network of macromolecules that provides structural support for the cells and tissues. Accumulated knowledge clearly demonstrated over the last decade that ECM plays key regulatory roles since it orchestrates cell signaling, functions, properties and morphology. Extracellularly secreted as well as cell-bound factors are among the major members of the ECM family. Proteins/glycoproteins, such as collagens, elastin, laminins and tenascins, proteo...
Source
#1Salvatore Santamaria (Imperial College London)H-Index: 14
#2Rens de Groot (UCL: University College London)H-Index: 1
Last. Rens de Groot (UCL: University College London)H-Index: 9
view all 2 authors...
The a disintegrin-like and metalloproteinase with thrombospondin motif (ADAMTS) family comprises 19 proteases that regulate the structure and function of extracellular proteins in the extracellular...
1 CitationsSource
#1Zihan MaH-Index: 1
#2Chenfeng MaoH-Index: 3
Last. Wei KongH-Index: 28
view all 5 authors...
Vascular remodeling is the adaptive response to various physiological and pathophysiological alterations that are closely related to aging and vascular diseases. Understanding the mechanistic regulation of vascular remodeling may be favorable for discovering potential therapeutic targets and strategies. The extracellular matrix (ECM), including matrix proteins and their degradative metalloproteases, serves as the main component of the microenvironment and exhibits dynamic changes during vascular...
2 CitationsSource
#1Stylianos Z. Karoulias (ISMMS: Icahn School of Medicine at Mount Sinai)H-Index: 3
#2Nandaraj Taye (ISMMS: Icahn School of Medicine at Mount Sinai)H-Index: 3
Last. Dirk Hubmacher (ISMMS: Icahn School of Medicine at Mount Sinai)H-Index: 19
view all 4 authors...
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...
5 CitationsSource
#1Anouar Hafiane (MUHC: McGill University Health Centre)H-Index: 18
Plaque development and rupture are hallmarks of atherosclerotic vascular disease. Despite current therapeutic developments, there is an unmet necessity in the prevention of atherosclerotic vascular disease. It remains a challenge to determine at an early stage if atherosclerotic plaque will become unstable and vulnerable. The arrival of molecular imaging is receiving more attention, considering it allows for a better understanding of the biology of human plaque and vulnerabilities. Various plaqu...
15 CitationsSource
#1Lauren W. WangH-Index: 19
#2Sumeda NandadasaH-Index: 9
Last. Suneel S. ApteH-Index: 72
view all 7 authors...
: The secreted metalloprotease ADAMTS9 has dual roles in extracellular matrix (ECM) turnover and biogenesis of the primary cilium during mouse embryogenesis. Its gene locus is associated with several human traits and disorders, but ADAMTS9 has few known interacting partners or confirmed substrates. Here, using a yeast two-hybrid screen for proteins interacting with its C-terminal Gon1 domain, we identified three putative ADAMTS9-binding regions in the ECM glycoprotein fibronectin. Using solid-ph...
9 CitationsSource