NMR conformational and dynamic consequences of a gly to ser substitution in an osteogenesis imperfecta collagen model peptide.
Close packing of three chains in a standard collagen triple helix requires Gly as every third residue. Missense mutations replacing one Gly by a larger residue in the tripeptide repeating sequence in type I collagen are common molecular causes of osteogenesis imperfecta. The structural and dynamic consequences of such mutations are addressed here by NMR studies on a peptide with a Gly-to-Ser substitution within an alpha1(I) sequence. Distances derived from nuclear Overhauser effects indicate that the three Ser residues are still packed in the center of the triple helix and that the standard 1-residue stagger is maintained. NMR dynamics using H-exchange and temperature-dependent amide chemical shifts indicate a greater disruption of hydrogen bonding and/or increased conformational flexibility C-terminal to the Ser site when compared with N terminal. This is consistent with recent suggestions relating clinical severity with an asymmetric effect of residues N- versus C-terminal to a mutation site. Dynamic studies also indicate that the relative position between a Gly in one chain and the mutation site in a neighboring staggered chain influences the disruption of the standard hydrogen-bonding pattern. The structural and dynamic alterations reported here may play a role in the etiology of osteogenesis imperfecta by affecting collagen secretion or interactions with other matrix molecules.
Li
Yingjie
Y
Department of Chemistry and Chemical Biology, BIOMAPS Institute, Rutgers, the State University of New Jersey, Piscataway, New Jersey 08854, USA.
Brodsky
Barbara
B
Baum
Jean
J
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics*; D003094:Collagen / Q000737:chemistry / Q000235:genetics*; D005998:Glycine / Q000235:genetics*; D006859:Hydrogen; D009682:Magnetic Resonance Spectroscopy; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010013:Osteogenesis Imperfecta / Q000235:genetics*; D010455:Peptides / Q000737:chemistry* / Q000235:genetics*; D011487:Protein Conformation; D012694:Serine / Q000235:genetics*; D013696:Temperature
D010455:Peptides; D012694:Serine; D006859:Hydrogen; D003094:Collagen; D005998:Glycine