Abstract
Fibrillar collagen molecules are synthesized as precursors, procollagens, with large propeptide extensions. While a homotrimeric form (three α1 chains) has been reported in embryonic tissues as well as in diseases (cancer, fibrosis, genetic disorders), collagen type I usually occurs as a heterotrimer (two α1 chains and one α2 chain). Inside the cell, the role of the C-terminal propeptides is to gather together the correct combination of three α chains during molecular assembly, but how this occurs for different forms of the same collagen type is so far unknown. Here, by structural and mutagenic analysis, we identify key amino acid residues in the α1 and α2 C-propeptides that determine homo- and heterotrimerization. A naturally occurring mutation in one of these alters the homo/heterotrimer balance. These results show how the C-propeptide of the α2 chain has specifically evolved to permit the appearance of heterotrimeric collagen I, the major extracellular building block among the metazoa.
Highlights
Fibrillar collagen molecules are synthesized as precursors, procollagens, with large propeptide extensions
We recently revealed the structural basis of chain recognition by determining the first three-dimensional (3D) structure of a C-propeptide trimer, that of human procollagen III (CPIII), an obligate homotrimer[28]
The structure of homo-C-propeptides of procollagen I (CPI) presented here provides a structural explanation for why it is that different fibrillar collagens can be synthesized in the same cell without mixing up of a chains from different genetic types, such as for example collagens I and III
Summary
Fibrillar collagen molecules are synthesized as precursors, procollagens, with large propeptide extensions. A naturally occurring mutation in one of these alters the homo/heterotrimer balance These results show how the C-propeptide of the a2 chain has evolved to permit the appearance of heterotrimeric collagen I, the major extracellular building block among the metazoa. We recently revealed the structural basis of chain recognition by determining the first three-dimensional (3D) structure of a C-propeptide trimer, that of human procollagen III (CPIII), an obligate homotrimer[28] Within this structure, the two parts of the CRS appeared on opposite sides of each interaction interface between adjacent chains, explaining the specificity of chain association. We present data on the corresponding heterotrimer (hetero-CPI) that reveal how a naturally occurring missense mutation in the a1(I) C-propeptide alters the homotrimer/ heterotrimer balance and how the sequence of the a2(I) C-propeptide is perfectly adapted to the formation of the [a1(I)]2a2(I) heterotrimer
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