Collagen VI microfibrils are widespread in the human body and, in particular, in the extracellular matrix of musculoskeletal tissues. Mutations in the genes that encode collagen VI cause muscular dystrophy and collagen VI is overexpressed in the articular cartilage of patients with osteoarthritis. One proteolytic fragment of collagen VI, endotrophin, has been described to serve as a potent adipokine, that contributes to tumor growth, fibrosis, inflammation and insulin resistance. The unusual structure of collagen VI contains only a short triple helix and, predominantly, globular von Willebrand-factor type-A (VWA) domains. Three different polypeptide chains combine intra- und extracellularly in a complex sequence of interactions and proteolytic cleavages to form the secreted 2200 kDa tetramer of monomeric trimers.

We study the structure and assembly of collagen VI, in part at atomic resolution. The purpose is to understand pathomechanisms of collagen VI-dependent musculoskeletal diseases. This may allow future therapeutic approaches. We further study the release, cell binding, cellular uptake and effects of biologically active fragments of collagen VI, such as endotrophin. We want to understand the signaling functions of collagen VI and lay a better foundation for the use of collagen VI fragments as biomarkers for human disease.

Selected publications

1. Seifer P, Hay E, Fleischhauer L, Heilig J, Bloch W, Sonntag S, Shmerling D, Clausen-Schaumann H, Aszodi A, Niehoff A, Cohen-Solal M, Paulsson M, Wagener R, Zaucke F. The Matrilin-3 T298M Mutation Predisposes for Post-Traumatic Osteoarthritis in a Knock-in Mouse Model. Osteoarthritis Cartilage 29, 78-88 (2021)
2. Imhof T, Korkmaz Y, Koch M, Sengle G, Schiavinato A. EMILIN proteins are novel extracellular constituents of the dentin-pulp complex. Sci Rep. 10, 15320 (2020)
3. Solomon-Degefa H, Gebauer JM, Jeffries CM, Freiburg CD, Meckelburg P, Bird LE, Baumann U, Svergun DI, Owens RO, Werner JM, Behrmann E, Paulsson M, Wagener R. Structure of a collagen VI α3 chain VWA domain array: adaptability and functional implications of myopathy causing mutations. J Biol Chem. 295, 12755-12771 (2020)
4. Heumüller SE, Talantikite M, Napoli M, Armengaud J, Mörgelin M, Hartmann U, Sengle G, Paulsson M, Moali C, Wagener R. C-terminal proteolysis of the collagen VI α3 chain by BMP-1 and proprotein convertase(s) releases endotrophin in fragments of different sizes J Biol Chem. 294, 13769-13780 (2019)
5. Bolduc V, Foley A. R, Solomon-Degefa H, Sarathy A, Donkervoort S, Hu Y, Chen GS, Sizov K, Nalls M, Zhou H, Aguti S, Cummings BB, Lek M, Tukiainen T, Marshall JL, Regev O, Marek-Yagel D, Sarkozy A, Butterfield RJ, Jou C, Jimenez-Mallebrera C, Li Y, Gartioux C, Mamchaoui K, Allamand V, Gualandi F, Ferlini A,  Hanssen E , the COL6A1 Intron Study Group, Wilton SD, Lamandé SR, MacArthur DG, Wagener R, Muntoni F, Bönnemann CG. A recurrent COL6A1 pseudoexon insertion causes muscular dystrophy and is effectively targeted by splice-correction therapies. JCI Insight, 4, e124403 (2019)
6. van der Ven AT, Kobbe B, Kohl S, Shril S, Pogoda HM, Imhof T, Ityel H, Vivante A, Chen J, Hwang DY, Connaughton DM, Mann N, Widmeier E, Taglienti M, Schmidt JM, Nakayama M, Senguttuvan P, Kumar S, Tasic V, Kehinde EO, Mane SM, Lifton RP, Soliman N, Lu W, Bauer SB, Hammerschmidt M, Wagener R, Hildebrandt FA homozygous missense mutation in VWA2, encoding an interactor of the Fraser-complex, in a patient with vesicoureteral reflux. PLoS One. 13, e0191224 (2018)
7. Maaß T, Bayley CP, Mörgelin M, Lettmann S, Bonaldo P, Paulsson M, Baldock C, Wagener R. Heterogeneity of Collagen VI Microfibrils: Structural Analysis of Non-collagenous Regions. J Biol Chem. 291, 5247-58 (2016)
8. Lettmann S, Bloch W, Maaß T, Niehoff A, Schulz JN, Eckes B, Eming SA, Bonaldo P, Paulsson M, Wagener R. Col6a1 Null Mice as a Model to Study Skin Phenotypes in Patients with Collagen VI Related Myopathies: Expression of Classical and Novel Collagen VI Variants during Wound Healing. PLoS One 9, e105686 (2014)
9. Becker AK, Mikolajek H, Paulsson M, Wagener R, Werner JM. A novel structure of a collagen VI VWA-domain displays N- and C-termini at opposite sides of the protein. Structure 22 199-208 (2014)
10. Schiavinato A, Becker AK, Zanetti M, Corallo D, Milanetto M, Bizzotto D, Bressan G, Guljelmovic M, Paulsson M, Wagener R, Braghetta P, Bonaldo P. EMILIN-3, peculiar member of elastin microfibril interface-located protein (EMILIN) family, has distinct expression pattern, forms oligomeric assemblies, and serves as transforming growth factor β (TGF-β) antagonist. J Biol Chem. 287, 11498-515 (2012)