Collagen VI is a heterotrimeric, ubiquitously expressed microfibrillar collagen with a complex intracellular and extracellular assembly process. In addition to a short collagenous region, it is primarily composed of von Willebrand factor A (VWA) domains. Notably, only the C-terminal end of the α3 chain contains other domain types, including a Kunitz-like C5 domain, which has been reported to be necessary for microfibril formation, to function as a matrikine and exhibit biomarker properties. This region of the α3 chain undergoes proteolytic processing, with cleavage sites identified for proprotein convertases, matrix metalloproteinases (MMPs), and bone morphogenetic protein 1 (BMP1). Cleavage by furin-like convertases results in the generation of a mature collagen VI α3 chain lacking its 70 kDa C2-C5 domains. Here, we provide the first characterization of the functional significance of the furin-like cleavage site, demonstrating that while it is constitutively used, it is not essential for collagen VI assembly, microfibril formation, or skeletal muscle function under physiological conditions, likely due to the presence of redundant cleavage sites. We also present an initial characterization of the biological activity of the released fragments on myoblast cultures showing that they do not affect C2C12 myoblast behaviour or differentiation. These findings deepen our understanding of α3 chain processing and highlight its potential significance for collagen VI assembly and function, including the generation of peptides with potential biomarker and biological activity properties.
Keywords: Collagen VI; Endotrophin; Furin; Proprotein convertases.
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