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

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

doi:10.1073/pnas.070050097

Cited by 180 publications

(221 citation statements)

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“…This selection bias that was also recently observed by Pepin et al 13 cannot be explained by the transition/transversion rate bias in the human coding sequences and is positively correlated to the triple helix destabilizing effect of the corresponding variants. 14 The collagen triple helical structure is indeed disrupted more profoundly when Gly is replaced by a large charged amino acid such as Asp, than by a smaller residue such as Ala. A recent in vitro study tested the effect of two types of missense variants (Gly-to-Val and Gly-to-Ala) on the type III collagen folding using a bacterial system for production of homotrimeric model polypeptides. 15 The effect of the Gly-to-Val variant was stronger compared with Gly-to-Ala, suggesting that some Ala variants might not be severe enough to cause vEDS.…”

Section: Discussionmentioning

confidence: 99%

The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers–Danlos syndrome

et al. 2015

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Vascular Ehlers-Danlos syndrome (vEDS) is a rare and severe autosomal dominant disorder caused by variants at the COL3A1 gene. Clinical characteristics and course of disease of 215 molecularly proven patients (146 index cases and 69 relatives) were analysed. We found 126 distincts variants that were divided into five groups: (1) Glycine substitutions (n = 71), (2) splice-site and in-frame insertions-deletions (n = 36), (3) variants leading to haplo-insufficiency (n = 7), (4) non-glycine missense variants within the triple helix (n = 4 variants), and (5) non-glycine missense variants or in-frame insertions-deletions, in the N-or C-terminal part of the protein (n = 8). Overall, our cohort confirmed the severity of the disease with a median age at first complication of 29 years (IQR 22-39), the most frequent being arterial (48%) and digestive (24%) ruptures. Groups 2 and 1 were significantly more severe than groups 3-5, with extreme median ages at first major complication of 23-47 years. Patients of groups 3-5 had a less typical phenotype and remarkably absence of digestive events. The distribution of glycine-replacing amino acids was strongly biased towards more destabilizing residues of the collagen assembly. Thus the natural course of vEDS and the clinical phenotype of patients are influenced by the type of COL3A1 variant. This study also confirms that patients with variants located in the C-and N-termini or leading to haplo-insufficiency have milder course of the disease and less prevalent diagnostic criteria. These findings may help refine diagnostic strategy, genetic counselling and clinical care.

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Section: Discussionmentioning

confidence: 99%

The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers–Danlos syndrome

et al. 2015

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“…Thermostability measurements of peptides modeling Gly mutations (20) revealed that the substitutions predicted to be lethal by the decision tree (Arg, Val, Glu, and Asp) are more disruptive to triple-helical structure than those predicted to be nonlethal (Ala and Ser). Cys substitutions, predicted to have both lethal and nonlethal mutations in this region, have intermediate thermostability.…”

Section: Predicting Lethality From Position and Amino Acidmentioning

confidence: 99%

“…One approach has been to estimate sequencespecific effects on local stability using the melting temperature (T m ) of collagen-like peptides. T m values were determined systematically for two sets of host-guest peptides, one modeling amino acid substitutions for Gly (20) and a second measuring the relative stability of 82 different Gly-X-Y triplets (21). Using data from the former set, a correlation was found between OI phenotype of COL1A1 mutations and the destabilization induced by the substitutions (20).…”

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confidence: 99%

“…T m values were determined systematically for two sets of host-guest peptides, one modeling amino acid substitutions for Gly (20) and a second measuring the relative stability of 82 different Gly-X-Y triplets (21). Using data from the former set, a correlation was found between OI phenotype of COL1A1 mutations and the destabilization induced by the substitutions (20). However, using data from the Gly-X-Y set, the local stability around a mutation site, approximated as the average T m of the neighboring triplets, did not show a clear association with clinical severity (21).…”

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confidence: 99%

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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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“…Studies on host-guest peptides (Gly-Pro-Hyp) 3 -Gly-Pro-Hyp-(Gly-Pro-Hyp) 4 with the central Gly replaced by residues obtained by a single base substitution indicated that all Gly replacements were highly destabilizing and the degree of triple-helix destabilization depends on the identity of the residue replacing Gly, with the order Ala, Ser\Cys\Arg\Val\Glu, Asp. 45 The crystal structure of a (Pro-Hyp-Gly) 10 peptide containing one Gly to Ala replacement shows a loss of direct hydrogen bonds at the Ala site, a local untwisting of the helix, and a loss of register between the two triple-helical ends. 21 OI collagens with a Gly missense mutation have a delay in folding 46 and model peptides indicated that such a Gly replacement will arrest C-to N-terminal triple-helix folding unless there is a strong renucleation site downstream of the mutation.…”

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confidence: 99%

Triple‐helical peptides: An approach to collagen conformation, stability, and self‐association

et al. 2008

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Peptides have been an integral part of the collagen triple‐helix structure story, and have continued to serve as useful models for biophysical studies and for establishing biologically important sequence‐structure‐function relationships. High resolution structures of triple‐helical peptides have confirmed the basic Ramachandran triple‐helix model and provided new insights into the hydration, hydrogen bonding, and sequence dependent helical parameters in collagen. The dependence of collagen triple‐helix stability on the residues in its (Gly‐X‐Y)n repeating sequence has been investigated by measuring melting temperatures of host‐guest peptides and an on‐line collagen stability calculator is now available. Although the presence of Gly as every third residue is essential for an undistorted structure, interruptions in the repeating (Gly‐X‐Y)n amino acid sequence pattern are found in the triple‐helical domains of all nonfibrillar collagens, and are likely to play a role in collagen binding and degradation. Peptide models indicate that small interruptions can be incorporated into a rod‐like triple‐helix with a highly localized effect, which perturbs hydrogen bonds and places the standard triple‐helices on both ends out of register. In contrast to natural interruptions, missense mutations which replace one Gly in a triple‐helix domain by a larger residue have pathological consequences, and studies on peptides containing such Gly substitutions clarify their effect on conformation, stability, and folding. Recent studies suggest peptides may also be useful in defining the basic principles of collagen self‐association to the supramolecular structures found in tissues. © 2008 Wiley Periodicals, Inc. Biopolymers 89: 345–353, 2008.This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

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

Cited by 180 publications

References 54 publications

The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers–Danlos syndrome

The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers–Danlos syndrome

Predicting the Clinical Lethality of Osteogenesis Imperfecta from Collagen Glycine Mutations

Triple‐helical peptides: An approach to collagen conformation, stability, and self‐association

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