title: Osteogenesis imperfecta missense mutations in collagen: structural consequences of a glycine to alanine replacement at a highly charged site.
abstract: Glycine is required as every third residue in the collagen triple helix, and a missense mutation leading to the replacement of even one Gly in the repeating (Gly-Xaa-Yaa)(n) sequence with a larger residue leads to a pathological condition. Gly to Ala missense mutations are highly underrepresented in osteogenesis imperfecta (OI) and other collagen diseases, suggesting that the smallest replacement residue, Ala, might cause the least structural perturbation and mildest clinical consequences. The relatively small number of Gly to Ala mutation sites that do lead to OI must have some unusual features, such as greater structural disruption because of local sequence environment or location at a biologically important site. Here, peptides are used to model a severe OI case in which a Gly to Ala mutation is found within a highly stabilizing Lys-Gly-Asp sequence environment. Nuclear magnetic resonance, circular dichroism, and differential scanning calorimetry studies indicate this Gly to Ala replacement leads to a substantial loss of triple-helix stability and nonequivalence of the Ala residues in the three chains such that only one of the three Ala residues is capable of forming a good backbone hydrogen bond. Examination of reported OI Gly to Ala mutations suggests their preferential location at known collagen binding sites, and we propose that structural defects caused by Ala replacements may lead to pathology when they interfere with interactions.
authors: Department of Chemistry and Chemical Biology, BIOMAPS Institute, Rutgers University, Piscataway, New Jersey 08854, United States.
authors: Jianxi
authors: J
authors: Xiao
authors: Haiming
authors: H
authors: Cheng
authors: Teresita
authors: T
authors: Silva
authors: Jean
authors: J
authors: Baum
authors: Barbara
authors: B
authors: Brodsky
mesh_terms: D000409:Alanine / Q000737:chemistry*; D019943:Amino Acid Substitution; D002152:Calorimetry, Differential Scanning; D002942:Circular Dichroism; D024042:Collagen Type I / Q000737:chemistry* / Q000235:genetics*; D000090602:Collagen Type I, alpha 1 Chain; D005998:Glycine / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D050505:Mutant Proteins / Q000737:chemistry; D020125:Mutation, Missense; D019906:Nuclear Magnetic Resonance, Biomolecular; D010013:Osteogenesis Imperfecta / Q000235:genetics*; D010446:Peptide Fragments / Q000737:chemistry; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D017433:Protein Structure, Secondary; D044366:Transition Temperature
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D050505:Mutant Proteins; D010446:Peptide Fragments; D000409:Alanine; D005998:Glycine