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The multiple, complex roles of versican and its proteolytic turnover by ADAMTS proteases during embryogenesis.

ABSTRACT: Embryonic development is an exceptionally dynamic process, requiring a provisional extracellular matrix that is amenable to rapid remodeling, and proteolytic or non-proteolytic mechanisms that can remodel the major components of this matrix. Versican is a chondroitin-sulfate proteoglycan that forms highly hydrated complexes with hyaluronan and is widely distributed in the provisional matrix of mammalian embryos. It has been extensively studied in the context of cardiovascular morphogenesis, neural crest cell migration and skeletal development. Analysis of Vcan transgenic mice has established the requirement for versican in cardiac development and its role in skeletogenesis. The ADAMTS family includes several versican-degrading proteases that are active during remodeling of the embryonic provisional matrix, especially during sculpting of versican-rich tissues. Versican is cleaved at specific peptide bonds by ADAMTS proteases, and the cleavage products are detectable by neo-epitope antibodies. Myocardial compaction, closure of the secondary palate (in which neural crest derived cells participate), endocardial cushion remodeling, myogenesis and interdigital web regression are developmental contexts in which ADAMTS-mediated versican proteolysis has been identified as a crucial requirement. ADAMTS proteases are expressed coordinately and function cooperatively in many of these contexts. In addition to versican clearance, ADAMTS proteases generate a bioactive versican fragment containing the N-terminal G1 domain, which we have named versikine. This review promotes the view that the embryonic extracellular matrix has evolved not only to provide a permissive environment for embryo growth and morphogenesis, but through its dissolution to influence and regulate cellular processes.

SUBMITTER: Nandadasa S

PROVIDER: S-EPMC5525047 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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The multiple, complex roles of versican and its proteolytic turnover by ADAMTS proteases during embryogenesis.

Nandadasa Sumeda S Foulcer Simon S Apte Suneel S SS

Matrix biology : journal of the International Society for Matrix Biology 20140118

Embryonic development is an exceptionally dynamic process, requiring a provisional extracellular matrix that is amenable to rapid remodeling, and proteolytic or non-proteolytic mechanisms that can remodel the major components of this matrix. Versican is a chondroitin-sulfate proteoglycan that forms highly hydrated complexes with hyaluronan and is widely distributed in the provisional matrix of mammalian embryos. It has been extensively studied in the context of cardiovascular morphogenesis, neur ...[more]

PMID: 24444773

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Project description:Essentials Recently, ADAMTS-13 has been shown to undergo substrate induced conformation activation. Conformational quiescence of ADAMTS-13 may serve to prevent off-target proteolysis in plasma. Conformationally active ADAMTS-13 variants are capable of proteolysing the Aα chain of fibrinogen. This should be considered as ADAMTS-13 variants are developed as potential therapeutic agents. Click to hear Dr Zheng's presentation on structure function and cofactor-dependent regulation of ADAMTS-13 SUMMARY: Background Recent work has revealed that ADAMTS-13 circulates in a 'closed' conformation, only fully interacting with von Willebrand factor (VWF) following a conformational change. We hypothesized that this conformational quiescence also maintains the substrate specificity of ADAMTS-13 and that the 'open' conformation of the protease might facilitate proteolytic promiscuity. Objectives To identify a novel substrate for a constitutively active gain of function (GoF) ADAMTS-13 variant (R568K/F592Y/R660K/Y661F/Y665F). Methods Fibrinogen proteolysis was characterized using SDS PAGE and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Fibrin formation was monitored by turbidity measurements and fibrin structure visualized by confocal microscopy. Results ADAMTS-13 exhibits proteolytic activity against the Aα chain of human fibrinogen, but this is only manifest on its conformational activation. Accordingly, the GoF ADAMTS-13 variant and truncated variants such as MDTCS exhibit this activity. The cleavage site has been determined by LC-MS/MS to be Aα chain Lys225-Met226. Proteolysis of fibrinogen by GoF ADAMTS-13 impairs fibrin formation in plasma-based assays, alters clot structure and increases clot permeability. Although GoF ADAMTS-13 does not appear to proteolyse preformed cross-linked fibrin, its proteolytic activity against fibrinogen increases the susceptibility of fibrin to tissue-type plasminogen activator (t-PA)-induced lysis by plasmin and increases the fibrin clearance rate more than 8-fold compared with wild-type (WT) ADAMTS-13 (EC50 values of 3.0 ± 1.7 nm and 25.2 ± 9.7 nm, respectively) in in vitro thrombosis models. Conclusion The 'closed' conformation of ADAMTS-13 restricts its specificity and protects against fibrinogenolysis. Induced substrate promiscuity will be important as ADAMTS-13 variants are developed as potential therapeutic agents against thrombotic thrombocytopenic purpura (TTP) and other cardiovascular diseases.

Dataset Information

The multiple, complex roles of versican and its proteolytic turnover by ADAMTS proteases during embryogenesis.

Publications

The multiple, complex roles of versican and its proteolytic turnover by ADAMTS proteases during embryogenesis.

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