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Structural basis of homo- and heterotrimerization of collagen I.

ABSTRACT: Fibrillar collagen molecules are synthesized as precursors, procollagens, with large propeptide extensions. While a homotrimeric form (three ?1 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 ?1 chains and one ?2 chain). Inside the cell, the role of the C-terminal propeptides is to gather together the correct combination of three ? 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 ?1 and ?2 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 ?2 chain has specifically evolved to permit the appearance of heterotrimeric collagen I, the major extracellular building block among the metazoa.

SUBMITTER: Sharma U

PROVIDER: S-EPMC5353611 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Structural basis of homo- and heterotrimerization of collagen I.

Sharma Urvashi U Carrique Loïc L Vadon-Le Goff Sandrine S Mariano Natacha N Georges Rainier-Numa RN Delolme Frederic F Koivunen Peppi P Myllyharju Johanna J Moali Catherine C Aghajari Nushin N Hulmes David J S DJ

Nature communications 20170310

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 occu ...[more]

PMID: 28281531

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Project description:Normal type I collagen is a heterotrimer of two alpha1(I) and one alpha2(I) chains, but various genetic and environmental factors result in synthesis of homotrimers that consist of three alpha1(I) chains. The homotrimers completely replace the heterotrimers only in rare recessive disorders. In the general population, they may compose just a small fraction of type I collagen. Nevertheless, they may play a significant role in pathology; for example, synthesis of 10-15% homotrimers due to a polymorphism in the alpha1(I) gene may contribute to osteoporosis. Homotrimer triple helices have different stability and less efficient fibrillogenesis than heterotrimers. Their fibrils have different mechanical properties. However, very little is known about their molecular interactions and fibrillogenesis in mixtures with normal heterotrimers. Here we studied the kinetics and thermodynamics of fibril formation in such mixtures by combining traditional approaches with 3D confocal imaging of fibrils, in which homo- and heterotrimers were labeled with different fluorescent colors. In a mixture, following a temperature jump from 4 to 32 degrees C, we observed a rapid increase in turbidity most likely caused by formation of homotrimer aggregates. The aggregates promoted nucleation of homotrimer fibrils that served as seeds for mixed and heterotrimer fibrils. The separation of colors in confocal images indicated segregation of homo- and heterotrimers at a subfibrillar level throughout the process. The fibril color patterns continued to change slowly after the fibrillogenesis appeared to be complete, due to dissociation and reassociation of the pepsin-treated homo- and heterotrimers, but this remixing did not significantly reduce the segregation even after several days. Independent homo- and heterotrimer solubility measurements in mixtures confirmed that the subfibrillar segregation was an equilibrium property of intermolecular interactions and not just a kinetic phenomenon. We argue that the subfibrillar segregation may exacerbate effects of a small fraction of alpha1(I) homotrimers on formation, properties, and remodeling of collagen fibers.

Dataset Information

Structural basis of homo- and heterotrimerization of collagen I.

Publications

Structural basis of homo- and heterotrimerization of collagen I.

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