Structural basis of fibrillar collagen trimerization and related genetic disorders

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Abstract

The C propeptides of fibrillar procollagens have crucial roles in tissue growth and repair by controlling both the intracellular assembly of procollagen molecules and the extracellular assembly of collagen fibrils. Mutations in C propeptides are associated with several, often lethal, genetic disorders affecting bone, cartilage, blood vessels and skin. Here we report the crystal structure of a C-propeptide domain from human procollagen III. It reveals an exquisite structural mechanism of chain recognition during intracellular trimerization of the procollagen molecule. It also gives insights into why some types of collagen consist of three identical polypeptide chains, whereas others do not. Finally, the data show striking correlations between the sites of numerous disease-related mutations in different C-propeptide domains and the degree of phenotype severity. The results have broad implications for understanding genetic disorders of connective tissues and designing new therapeutic strategies.

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Figure 1: Structure of the C-propeptide trimer of human procollagen III.
Figure 2: Details of the interaction interface.
Figure 3: Structural alignment of the three chains of the proα1(III) C-propeptide trimer.
Figure 4: Positions of known missense mutations in the C propeptides of fibrillar procollagens I, II, III and V, mapped onto the structure of the proα1(III) C propeptide.

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Acknowledgements

We thank F. Delolme, D. Eichenberger, K. El Omari, P. Gouet, R. Haser, R. Liddington, G. Parsiegla, X. Robert, G. Stranzl, S. Vadon-Le Goff, M. van Rest and T. Walter for their help and suggestions at different stages of the project. We also thank A. Chaboud and I. Grosjean of the Protein Production and Analysis facility (Unité Mixte de Service Biosciences Gerland-Lyon Sud 3444) as well as staff of Diamond Light Source for technical support. This work was funded by the Fondation de France (11878 to D.J.S.H.), the Agence National de la Recherche (ANR 07 PHYSIO 022 01 to D.J.S.H.; ANR 2010 BLAN 1526 01 to C.M. and N.A.), the European Commission (227764 to E.Y.J.), the Medical Research Council UK (G09 000 84 to E.Y.J.), Cancer Research UK (A5261 to E.Y.J.) and the Centre National de la Recherche Scientifique, Université Lyon 1 and Lyonbiopôle.

Author information

J.-M.B., N.M., Y.Z., K.H. and D.J.S.H. designed and performed the research; J.M.B., J.-Y.E., E.Y.J., C.M., N.A. and D.J.S.H. analyzed the data; and D.J.S.H. wrote the paper.

Correspondence to David J S Hulmes.

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This work forms part of a US patent application by J.M.B., N.M., C.M., N.A. and D.J.S.H.

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Supplementary Text and Figures

Supplementary Figures 1–4 and Supplementary Table 1 (PDF 1130 kb)

Supplementary Movie 1

Positions of known missense mutations in the C-propeptides of fibrillar procollagens I, II, III and V mapped on to the structure of the proa1(III) C-propeptide (MPG 6429 kb)

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Bourhis, J., Mariano, N., Zhao, Y. et al. Structural basis of fibrillar collagen trimerization and related genetic disorders. Nat Struct Mol Biol 19, 1031–1036 (2012) doi:10.1038/nsmb.2389

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