Amino Acid Sequence Environment Modulates the Disruption by Osteogenesis Imperfecta Glycine Substitutions in Collagen-like Peptides
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- 作者：Wei Yang ; Madhavi L. Battineni ; and Barbara Brodsky
- 刊名：Biochemistry
- 出版年：1997
- 出版时间：June 10, 1997
- 年：1997
- 卷：36
- 期：23
- 页码：6930 - 6935
- 全文大小：216K
- 年卷期：v.36,no.23(June 10, 1997)
- ISSN：1520-4995
文摘
Ostoegenesis imperfecta (OI) or "brittle bone" disease isassociated with mutations in thegenes for type I collagen chains and produces variable phenotypes,ranging from lethal cases at birth tomild cases with increased bone fractures. The most common OImutations are single base substitutionsleading to replacement of Gly by another residue, breaking the typical(Gly-X-Y)n repeating sequencepattern of the collagen triple-helix. Triple-helical peptides weredesigned to focus on residues 892-921of the 
lpha.gif" BORDER=0>1 chain of type I collagen, where two OI Gly
Ser mutationsare found in close proximity, a mildmutation at site 901 and a lethal mutation at site 913. Peptideswere designed to include amino acidsequences around these mutation sites, and were synthesized with thenormal sequence or with the GlySermutated sequence. The peptide including the normal sequenceresidues 892-909 with four Gly-Pro-Hyptriplets at the C-terminus formed a stable triple-helix, andintroduction of a Ser residue for Gly at the 901mutation site led to a 50% loss of triple-helix content and a decreasein thermal stability, with little effecton folding. A peptide including residues 904-921 again formed astable triple-helix, but the introductionof the GlySer substitution at site 913 led to a much greaterdecrease in thermal stability. These studiesdemonstrate the impact of local sequences flanking the Gly substitutionon structural consequences andsupport the concept of variability and regional effects along thecollagen molecule.
lpha.gif" BORDER=0>1 chain of type I collagen, where two OI GlySer mutationsare found in close proximity, a mildmutation at site 901 and a lethal mutation at site 913. Peptideswere designed to include amino acidsequences around these mutation sites, and were synthesized with thenormal sequence or with the GlySermutated sequence. The peptide including the normal sequenceresidues 892-909 with four Gly-Pro-Hyptriplets at the C-terminus formed a stable triple-helix, andintroduction of a Ser residue for Gly at the 901mutation site led to a 50% loss of triple-helix content and a decreasein thermal stability, with little effecton folding. A peptide including residues 904-921 again formed astable triple-helix, but the introductionof the GlySer substitution at site 913 led to a much greaterdecrease in thermal stability. These studiesdemonstrate the impact of local sequences flanking the Gly substitutionon structural consequences andsupport the concept of variability and regional effects along thecollagen molecule.