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B1 Raimund Wagener, Mats Paulsson, Alvise Schiavinato

Collagen VI assembly and function in musculoskeletal disorders

Prof. Dr. Raimund Wagener

Institute for Biochemistry II
Faculty of Medicine, University of Cologne
Joseph-Stelzmann-Str. 52, 50931 Cologne

 

Prof. Dr. Mats Paulsson

Institute for Biochemistry II
Faculty of Medicine, University of Cologne
Joseph-Stelzmann-Str. 52, 50931 Cologne

Dr. Alvise Schiavinato

Institute for Biochemistry II
Faculty of Medicine, University of Cologne
Joseph-Stelzmann-Str. 52, 50931 Cologne

Summary

Collagen VI microfibrils are widespread in the extracellular matrix (ECM) of musculoskeletal tissues. Mutations cause muscular dystrophies and collagen VI is upregulated in osteoarthritis. A fragment, “endotrophin”, acts as an adipokine enhancing tumor progression, fibrosis, inflammation and insulin resistance. The unusual structure of collagen VI is composed of only a short triple helix and predominant tandem arrays of globular von Willebrand factor type A (VWA) domains. Three different chains assemble intra- and extracellularly by a complex series of chain interactions and proteolytic cleavages. The secreted form is a 2,200 kDa tetramer of heterotrimeric monomers. Microfibrils also carry other proteins. We elucidate the interactions, assembly and degradation of collagen VI to reveal pathomechanisms in musculoskeletal disorders to allow the development of novel therapeutic approaches.

We express VWA domains of collagen VI to set up crystal trays and perform SAXS measurements to localize interaction surfaces and proteolytic cleavage sites. Patient-derived fibroblast cell lines carrying mutations in collagen VI chains or cell lines manipulated by CRISPR-Cas are used to define the disease-relevant steps in the assembly. Crucial interaction sites and cleavage sites will be mutated by CRISPR-Cas in mice to study pathomechanisms of musculoskeletal disorders in vivo.