title: 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 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.
authors.affiliation: Molecular Microbiology and Structural Biochemistry Unit, UMR 5086 CNRS - University of Lyon 1, 7 passage du Vercors, F-69367 Lyon, France.
authors.forename: Urvashi
authors.initials: U
authors.lastname: Sharma
authors.affiliation: Molecular Microbiology and Structural Biochemistry Unit, UMR 5086 CNRS - University of Lyon 1, 7 passage du Vercors, F-69367 Lyon, France.
authors.forename: Loïc
authors.initials: L
authors.lastname: Carrique
authors.affiliation: Tissue Biology and Therapeutic Engineering Unit, UMR 5305 CNRS - University of Lyon 1, 7 passage du Vercors, F-69367 Lyon, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Vadon-Le Goff
authors.affiliation: Tissue Biology and Therapeutic Engineering Unit, UMR 5305 CNRS - University of Lyon 1, 7 passage du Vercors, F-69367 Lyon, France.
authors.forename: Natacha
authors.initials: N
authors.lastname: Mariano
authors.affiliation: Tissue Biology and Therapeutic Engineering Unit, UMR 5305 CNRS - University of Lyon 1, 7 passage du Vercors, F-69367 Lyon, France.
authors.forename: Rainier-Numa
authors.initials: RN
authors.lastname: Georges
authors.affiliation: Tissue Biology and Therapeutic Engineering Unit, UMR 5305 CNRS - University of Lyon 1, 7 passage du Vercors, F-69367 Lyon, France.|SFR Biosciences - Protein Science Facility, University of Lyon 1, Ecole Normale Supérieure de Lyon, INSERM US8, CNRS UMS 3444, 50 Avenue Tony Garnier, F-69366 Lyon, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Delolme
authors.affiliation: Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, P.O. Box 5000, FI-90014 Oulu, Finland.
authors.forename: Peppi
authors.initials: P
authors.lastname: Koivunen
authors.affiliation: Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, P.O. Box 5000, FI-90014 Oulu, Finland.
authors.forename: Johanna
authors.identifier: 0000-0001-7772-1250
authors.initials: J
authors.lastname: Myllyharju
authors.affiliation: Tissue Biology and Therapeutic Engineering Unit, UMR 5305 CNRS - University of Lyon 1, 7 passage du Vercors, F-69367 Lyon, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Moali
authors.affiliation: Molecular Microbiology and Structural Biochemistry Unit, UMR 5086 CNRS - University of Lyon 1, 7 passage du Vercors, F-69367 Lyon, France.
authors.forename: Nushin
authors.identifier: 0000-0002-2245-2679
authors.initials: N
authors.lastname: Aghajari
authors.affiliation: Tissue Biology and Therapeutic Engineering Unit, UMR 5305 CNRS - University of Lyon 1, 7 passage du Vercors, F-69367 Lyon, France.
authors.forename: David J S
authors.initials: DJ
authors.lastname: Hulmes
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D003001:Cloning, Molecular; D024042:Collagen Type I / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005822:Genetic Vectors / Q000737:chemistry / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: C000601279:COL1A2 protein, human; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D011994:Recombinant Proteins