Amino Acid Sequence Environment Modulates the Disruption by Osteogenesis Imperfecta Glycine Substitutions in Collagen-like Peptides

Yang, Wei; Battineni, Madhavi L.; Brodsky, Barbara

doi:10.1021/bi970051h

Cited by 65 publications

(77 citation statements)

References 39 publications

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“…The implication that Gly f Ser mutations with low T m [+1] values result in lower-than-expected stability is supported by experimental peptide results reported here (Table 6) and elsewhere (33). Lower stability, folding rate, and calorimetric enthalpy were observed for peptide GPOSPAGFA, with low T m [+1] and high T m [-1] values, than for peptide GFASPAGPO, with the positions of the high-and low-stability triplets reversed.…”

Section: Discussionsupporting

confidence: 85%

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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Section: Discussionsupporting

confidence: 85%

Predicting the Clinical Lethality of Osteogenesis Imperfecta from Collagen Glycine Mutations

et al. 2008

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“…In particular it has been observed that large and charged residues generally lead to more severe OI types. [7][8][9] Here we have shown that the local mechanical properties of single tropocollagen molecules can be predicted based on the physical properties of the replacing residue.…”

Section: Resultsmentioning

confidence: 96%

“…Some trends are apparent, such as OI severity increasing with an amino to carboxyl terminal orientation and with substitution by large and charged amino acids. [7][8][9] At present, however, genotype-phenotype correlations are too weak to accurately predict the phenotypic effect of a particular glycine mutation. Indeed, the answer to the question how a single point mutation in the tropocollagen molecule can cause the failure of the entire skeletal system still remains a mystery.…”

Section: Introductionmentioning

confidence: 99%

Single molecule effects of osteogenesis imperfecta mutations in tropocollagen protein domains

Gautieri¹,

Vesentini²,

Redaelli³

et al. 2008

Protein Science

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Osteogenesis imperfecta (OI) is a genetic disease characterized by fragile bones, skeletal deformities and, in severe cases, prenatal death that affects more than 1 in 10,000 individuals. Here we show by full atomistic simulation in explicit solvent that OI mutations have a significant influence on the mechanical properties of single tropocollagen molecules, and that the severity of different forms of OI is directly correlated with the reduction of the mechanical stiffness of individual tropocollagen molecules. The reduction of molecular stiffness provides insight into the molecular-scale mechanisms of the disease. The analysis of the molecular mechanisms reveals that physical parameters of side-chain volume and hydropathy index of the mutated residue control the loss of mechanical stiffness of individual tropocollagen molecules. We propose a model that enables us to predict the loss of stiffness based on these physical characteristics of mutations. This finding provides an atomistic-level mechanistic understanding of the role of OI mutations in defining the properties of the basic protein constituents, which could eventually lead to new strategies for diagnosis and treatment the disease. The focus on material properties and their role in genetic diseases is an important, yet so far only little explored, aspect in studying the mechanisms that lead to pathological conditions. The consideration of how material properties change in diseases could lead to a new paradigm that may expand beyond the focus on biochemical readings alone and include a characterization of material properties in diagnosis and treatment, an effort referred to as materiomics.

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“…Local sequences N-terminal to the mutation site could also influence the propensity for renucleation, if the Gly substitution has interrupted the C-to N-terminal propagation of the triple helix (40,41). Calculations of relative stabilities, assigned on the basis of the frequency of different tripeptides in collagen, suggest that mutations within a very stable local environment result in a more severe clinical effect (36,42), and studies on peptides have supported the influence of local triplets surrounding a mutation on its disruptive effect (43,44). Cooperative blocks that undergo local breathing or microunfolding could also be destabilized selectively by Gly substitutions and prevent folding of the molecule (2,12).…”

Section: Discussionmentioning

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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179

198

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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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Amino Acid Sequence Environment Modulates the Disruption by Osteogenesis Imperfecta Glycine Substitutions in Collagen-like Peptides

Cited by 65 publications

References 39 publications

Predicting the Clinical Lethality of Osteogenesis Imperfecta from Collagen Glycine Mutations

Predicting the Clinical Lethality of Osteogenesis Imperfecta from Collagen Glycine Mutations

Single molecule effects of osteogenesis imperfecta mutations in tropocollagen protein domains

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

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