The molecular mechanisms that guide collagen assembly are central to our understanding of collagen biosynthesis. Fundamental questions in this area, especially with respect to the molecular recognition events that allow collagen strands to form stable homotrimers or heterotrimers, remain unanswered. The ~30 kDa globular C-terminal propeptide domain of collagen is responsible for initiating collagen folding, and thus the principal interactions governing trimerization most likely reside within this domain. We use biochemical and biophysical approaches to explore key interactions that govern trimeric assembly of the C-propeptide, including the critical role of Ca2+ in non-covalent, trimeric assembly and the role of interchain disulfide bonds in immortalizing this trimer. We demonstrate that the presence or absence of a single cysteine in type-I collagen’s C-propeptide domain is an ancient and primary factor governing the ability of a given collagen polypeptide to stably homotrimerize. This simple cysteine-based code for stable assembly provides a molecular model that can be used to predict, a priori, the identity of not just collagen homotrimers, but also naturally occurring 2:1 and 1:1:1 heterotrimers across all fibrillary collagens. Additionally, we examine a panel of mutations within the C-propeptide of collagen-I known to cause osteogenesis imperfecta to understand how trimeric assembly is altered in these variants. We explore the biochemical origins of delayed or defective trimeric assembly caused by these point mutations within certain regions of the C-propeptide, including the Ca2+ binding site and cysteine code regions.

Molecular mechanisms of collagen C-propeptide assembly

256th National Meeting (2018)

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