Osteogenesis imperfecta missense mutations in collagen: Structural consequences of a glycine to alanine replacement at a highly charged site

Jianxi Xiao, Haiming Cheng, Teresita Silva, Jean Baum, Barbara Brodsky

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)10771-10780
Number of pages10
JournalBiochemistry
Volume50
Issue number50
DOIs
StatePublished - Dec 20 2011

Fingerprint

Osteogenesis Imperfecta
Missense Mutation
Alanine
Glycine
Collagen
Mutation
Pathology
Collagen Diseases
Differential scanning calorimetry
Differential Scanning Calorimetry
Hydrogen bonds
Circular Dichroism
Binding Sites
Nuclear magnetic resonance
Hydrogen
Defects
Peptides
Magnetic Resonance Spectroscopy

All Science Journal Classification (ASJC) codes

  • Biochemistry

Cite this

Xiao, Jianxi ; Cheng, Haiming ; Silva, Teresita ; Baum, Jean ; Brodsky, Barbara. / Osteogenesis imperfecta missense mutations in collagen : Structural consequences of a glycine to alanine replacement at a highly charged site. In: Biochemistry. 2011 ; Vol. 50, No. 50. pp. 10771-10780.
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Osteogenesis imperfecta missense mutations in collagen : Structural consequences of a glycine to alanine replacement at a highly charged site. / Xiao, Jianxi; Cheng, Haiming; Silva, Teresita; Baum, Jean; Brodsky, Barbara.

In: Biochemistry, Vol. 50, No. 50, 20.12.2011, p. 10771-10780.

Research output: Contribution to journalArticle

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AB - 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.

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