title: Position of single amino acid substitutions in the collagen triple helix determines their effect on structure of collagen fibrils.
abstract: Collagen II fibrils are a critical structural component of the extracellular matrix of cartilage providing the tissue with its unique biomechanical properties. The self-assembly of collagen molecules into fibrils is a spontaneous process that depends on site-specific binding between specific domains belonging to interacting molecules. These interactions can be altered by mutations in the COL2A1 gene found in patients with a variety of heritable cartilage disorders known as chondrodysplasias. Employing recombinant procollagen II, we studied the effects of R75C or R789C mutations on fibril formation. We determined that both R75C and R789C mutants were incorporated into collagen assemblies. The effects of the R75C and R789C substitutions on fibril formation differed significantly. The R75C substitution located in the thermolabile region of collagen II had no major effect on the fibril formation process or the morphology of fibrils. In contrast, the R789C substitution located in the thermostable region of collagen II caused profound changes in the morphology of collagen assemblies. These results provide a basis for identifying pathways leading from single amino acid substitutions in collagen II to changes in the structure of individual fibrils and in the organization of collagenous matrices.
authors.affiliation: Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Steplewski
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Ito
authors.forename: Eileen
authors.initials: E
authors.lastname: Rucker
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Brittingham
authors.forename: Tatiana
authors.initials: T
authors.lastname: Alabyeva
authors.forename: Milind
authors.initials: M
authors.lastname: Gandhi
authors.forename: Frank K
authors.initials: FK
authors.lastname: Ko
authors.forename: David E
authors.initials: DE
authors.lastname: Birk
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Jimenez
authors.forename: Andrzej
authors.initials: A
authors.lastname: Fertala
mesh_terms: D001665:Binding Sites; D003094:Collagen / Q000737:chemistry* / Q000648:ultrastructure; D005097:Exostoses, Multiple Hereditary / Q000235:genetics; D006801:Humans; D008666:Metalloendopeptidases / Q000737:chemistry; D046529:Microscopy, Electron, Transmission; D008954:Models, Biological; D009154:Mutation; D010003:Osteoarthritis / Q000235:genetics; D010434:Pepsin A / Q000737:chemistry; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry
chemical_list: D011994:Recombinant Proteins; D003094:Collagen; D010434:Pepsin A; D008666:Metalloendopeptidases; C039830:peptidyl-Lys metalloendopeptidase