Positional Preferences of Ionizable Residues in Gly-X-YTriplets of the Collagen Triple-helix

Chan, Virginia C.; Ramshaw, John A. M.; Kirkpatrick, Alan; Beck, Konrad; Brodsky, Barbara

doi:10.1074/jbc.272.50.31441

Cited by 86 publications

(83 citation statements)

References 37 publications

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“…Amino acid substitutions in thermostable domains, in contrast to the amino acid substitutions in thermolabile N-terminal domains, alter the termostability of the entire collagen molecule [Steplewski et al, 2004a]. In addition, the thermal stability of the triple-helix was found to depend strongly on the identity of the residue in the Yposition [Chan et al, 1997]. Phenotypes of patients with Arg792Gly and Arg789Cys substitutions, as well as protein studies of Arg789Cys collagen, suggest that mutations that alter arginine in the Y-position of the triplets located in the thermostable domains of collagen type II can result in very severe SEDC and SEMDC forms.…”

Section: Discussionmentioning

confidence: 94%

Novel amino acid substitution in the Y‐position of collagen type II causes spondyloepimetaphyseal dysplasia congenita

Sułko

Czarny-Ratajczak

Woźniak

et al. 2005

American J of Med Genetics Pt A

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We report on monozygotic twins with short stature and severe spondyloepimetaphyseal dysplasia congenita (SEMDC) from the Polish population. Phenotype of the twin girls resembles spondyloepiphyseal dysplasia congenita Spranger-Wiedemann (SEDC-SW), but shortening of the stature is more severe and the cranioface is normal. The distinctive radiographic features, in spite of similarity to SEDC-SW, indicate different spinal and, notably, severe metaphyseal involvement. Molecular analysis of the COL2A1 gene revealed an A to G transition at nucleotide þ79 of exon 41 that converted the codon for arginine at amino acid 792 to a codon for glycine (Arg792Gly). The twins were heterozygous for the mutation and neither parent had this change. The Arg792Gly substitution is located at the Y-position of Gly-X-Y triplet, and it is likely that this substitution decreased the thermal stability of the triple helix and may affect fibril growth by replacement of an arginine residue, which is important for a conformation of the triple helix.

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Section: Discussionmentioning

confidence: 94%

Novel amino acid substitution in the Y‐position of collagen type II causes spondyloepimetaphyseal dysplasia congenita

Sułko

Czarny-Ratajczak

Woźniak

et al. 2005

American J of Med Genetics Pt A

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“…(iv) Local stability was approximated by the relative thermostability of homotrimeric peptides. Multiple factors, including the mutation itself, the environment in the native protein, and the conditions of the experiment (39), could alter the relative T m values. Furthermore, the set of triplets with measured T m values is incomplete, and there may be unintentional bias in the selected sequences.…”

Section: Discussionmentioning

confidence: 99%

Predicting the Clinical Lethality of Osteogenesis Imperfecta from Collagen Glycine Mutations

et al. 2008

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Osteogenesis imperfecta (OI), or brittle bone disease, often results from missense mutation of one of the conserved glycine residues present in the repeating Gly-X-Y sequence characterizing the triplehelical region of type I collagen. A composite model was developed for predicting the clinical lethality resulting from glycine mutations in the R1 chain of type I collagen. The lethality of mutations in which bulky amino acids are substituted for glycine is predicted by their position relative to the N-terminal end of the triple helix. The effect of a Gly f Ser mutation is modeled by the relative thermostability of the Gly-X-Y triplet on the carboxy side of the triplet containing the substitution. This model also predicts the lethality of Gly f Ser and Gly f Cys mutations in the R2 chain of type I collagen. The model was validated with an independent test set of six novel Gly f Ser mutations. The hypothesis derived from the model of an asymmetric interaction between a Gly f Ser mutation and its neighboring residues was tested experimentally using collagen-like peptides. Consistent with the prediction, a significant decrease in stability, calorimetric enthalpy, and folding time was observed for a peptide with a low-stability triplet C-terminal to the mutation compared to a similar peptide with the low-stability triplet on the N-terminal side. The computational and experimental results together relate the position-specific effects of Gly f Ser mutations to the local structural stability of collagen and lend insight into the etiology of OI.Collagen is a fibrous protein that provides functional and structural integrity in the human body. Type I collagen, the major protein in bone, skin, and other tissues, is a heterotrimer comprised of two R1(I) and one R2(I) polypeptide chains, encoded by the COL1A1 and COL1A2 genes, respectively. Each chain includes 338 uninterrupted repeats of the Gly-X-Y triplet, where X and Y can be any amino acid but are most often proline and hydroxyproline (Hyp or O). 1 In the heterotrimeric protein, the Gly-X-Y repeats form the triple-helical structure that is characteristic of the collagen family. The conserved glycines in every third position are essential for the integrity of the protein since larger amino acids cannot be accommodated in the tightly packed core of the triple helix without disruption of the structure.Missense mutation of a conserved Gly in the triple-helical region of type I collagen generally leads to osteogenesis imperfecta (OI). OI, often called brittle bone disease, is characterized by bone fragility and increased susceptibility to fracture, which may be accompanied by bone deformity, decreased life span, dentinogenesis imperfecta, hearing loss, and altered scleral hue (1, 2). The disease presents in a wide array of phenotypes ranging from mild to lethal. The severity depends on the chain in which the Gly substitution occurs, the location within the chain, and the substituting amino acid (3), but it is not currently possible to predict reliably the lethality fr...

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“…Peptides were synthesized by using fluorenylmethoxycarbonyl chemistry, purified, and identified by mass spectrometry as described (19)(20)(21)(22).…”

Section: Methodsmentioning

confidence: 99%

Destabilization of osteogenesis imperfecta collagen-like model peptides correlates with the identity of the residue replacing glycine

Beck

Chan

Shenoy

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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Mutations resulting in replacement of one obligate Gly residue within the repeating (Gly-Xaa-Yaa) n triplet pattern of the collagen type I triple helix are the major cause of osteogenesis imperfecta (OI). Phenotypes of OI involve fragile bones and range from mild to perinatal lethal. In this study, host-guest triple-helical peptides of the form acetyl-(Gly-Pro-Hyp) 3-Zaa-Pro-Hyp-(Gly-Pro-Hyp)4-GlyGly-amide are used to isolate the influence of the residue replacing Gly on triple-helix stability, with Zaa ‫؍‬ Gly, Ala, Arg, Asp, Glu, Cys, Ser, or Val. Any substitution for Zaa ‫؍‬ Gly (melting temperature, Tm ‫؍‬ 45°C) results in a dramatic destabilization of the triple helix. For Ala and Ser, T m decreases to Ϸ10°C, and for the Arg-, Val-, Glu-, and Asp-containing peptides, Tm < 0°C. A Gly 3 Cys replacement results in T m < 0°C under reducing conditions but shows a broad transition (T m Ϸ 19°C) in an oxidizing environment. Addition of trimethylamine N-oxide increases T m by Ϸ5°C per 1 M trimethylamine N-oxide, resulting in stable triple-helix formation for all peptides and allowing comparison of relative stabilities. The order of disruption of different Gly replacements in these peptides can be represented as Ala < Ser < CPOred < Arg < Val < Glu < Asp. The rank of destabilization of substitutions for Gly in these Gly-ProHyp-rich homotrimeric peptides shows a significant correlation with the severity of natural OI mutations in the ␣1 chain of type I collagen.

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Positional Preferences of Ionizable Residues in Gly-X-YTriplets of the Collagen Triple-helix

Cited by 86 publications

References 37 publications

Novel amino acid substitution in the Y‐position of collagen type II causes spondyloepimetaphyseal dysplasia congenita

Novel amino acid substitution in the Y‐position of collagen type II causes spondyloepimetaphyseal dysplasia congenita

Predicting the Clinical Lethality of Osteogenesis Imperfecta from Collagen Glycine Mutations

Destabilization of osteogenesis imperfecta collagen-like model peptides correlates with the identity of the residue replacing glycine

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