Collagen Gly missense mutations: Effect of residue identity on collagen structure and integrin binding

Qiu, Yimin; Mekkat, Arya; Yu, Hongtao; Yiğit, Sezin; Hamaia, Samir; Farndale, Richard W.; Kaplan, David L.; Lin, Yu‐Shan; Brodsky, Barbara

doi:10.1016/j.jsb.2018.05.003

Cited by 27 publications

(19 citation statements)

References 55 publications

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“…A collagen triple helix is formed by three chains (two α1(I) chains and one α2(I) chain) supercoiling around the common axis and glycine, framing almost 338 Gly-Xaa-Yaa repeats in the region, is the only residue small enough to be accommodated in the limited interior of the helical space (Ramachandran and Kartha, 1955; Rich and Crick, 1961; Brodsky and Persikov, 2005). In the collagen triple helix, the Gly-substitution missense will produce structural deformation of the triple helix, leading to destabilization of the helical structure, affecting the synthesis of collagen ( Figure 4 ) (Brodsky and Persikov, 2005; Qiu et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Our four candidate mutations all locate in MLBR3, suggesting that they are most likely to be associated with OI. Structurally, different abnormalities in the collagen helix are associated with the identity of the residue replacing Gly (Bryan et al, 2011; Qiu et al, 2018), which also influence the severity of OI patients (residues replacing Gly of four candidate mutations: Asp, Arg, and Ser). Through the statistical analysis on the location of Gly-substitution mutations in a large number of OI patients, Beck et al found that all Gly→Asp in the α1(I) chain led to OI type II (perinatal lethal form) (Beck et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

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Genotype–Phenotype Association Analysis Reveals New Pathogenic Factors for Osteogenesis Imperfecta Disease

et al. 2019

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Osteogenesis imperfecta (OI), mainly caused by structural abnormalities of type I collagen, is a hereditary rare disease characterized by increased bone fragility and reduced bone mass. Clinical manifestations of OI mostly include multiple repeated bone fractures, thin skin, blue sclera, hearing loss, cardiovascular and pulmonary system abnormalities, triangular face, dentinogenesis imperfecta (DI), and walking with assistance. Currently, 20 causative genes with 18 subtypes have been identified for OI, of them, variations in COL1A1 and COL1A2 have been demonstrated to be major causative factors to OI. However, the complexity of the bone formation process indicates that there are potential new pathogenic genes associated with OI. To comprehensively explore the underlying mechanism of OI, we conducted association analysis between genotypes and phenotypes of OI diseases and found that mutations in COL1A1 and COL1A2 contributed to a large proportion of the disease phenotypes. We categorized the clinical phenotypes and the genotypes based on the variation types for those 155 OI patients collected from literature, and association study revealed that three phenotypes (bone deformity, DI, walking with assistance) were enriched in two variation types (the Gly-substitution missense and groups of frameshift, nonsense, and splicing variations). We also identified four novel variations (c.G3290A (p.G1097D), c.G3289C (p.G1097R), c.G3289A (p.G1097S), c.G3281A (p.G1094D)) in gene COL1A1 and two novel variations (c.G2332T (p.G778C), c.G2341T (p.G781C)) in gene COL1A2, which could potentially contribute to the disease. In addition, we identified several new potential pathogenic genes (ADAMTS2, COL5A2, COL8A1) based on the integration of protein–protein interaction and pathway enrichment analysis. Our study provides new insights into the association between genotypes and phenotypes of OI and novel information for dissecting the underlying mechanism of the disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genotype–Phenotype Association Analysis Reveals New Pathogenic Factors for Osteogenesis Imperfecta Disease

et al. 2019

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“…Previous studies have shown that substitution of these integral Gly residues causes structural deformities to the triple helix, and the extent of triple-helix destabilization depends on the amino acid substituted (30,31) and the surrounding sequence context (32)(33)(34)(35)(36). Recently, elegant studies have investigated the impact of Gly 3 Xaa mutations near integrinbinding sites in collagen I (31, 37) using recombinant bacterial collagen systems, which can incorporate long spans of collagenlike sequence and can probe selective mutation sites.…”

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confidence: 99%

Molecular underpinnings of integrin binding to collagen-mimetic peptides containing vascular Ehlers–Danlos syndrome–associated substitutions

Hoop

Kemraj

Wang

et al. 2019

Journal of Biological Chemistry

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Collagens carry out critical extracellular matrix (ECM) functions by interacting with numerous cell receptors and ECM components. Single glycine substitutions in collagen III, which predominates in vascular walls, result in vascular Ehlers-Danlos syndrome (vEDS), leading to arterial, uterine, and intestinal rupture and an average life expectancy of <50 years. Collagen interactions with integrin ␣ 2 ␤ 1 are vital for platelet adhesion and activation; however, how these interactions are impacted by vEDS-associated mutations and by specific amino acid substitutions is unclear. Here, we designed collagen-mimetic peptides (CMPs) with previously reported Gly 3 Xaa (Xaa ‫؍‬ Ala, Arg, or Val) vEDS substitutions within a high-affinity integrin ␣ 2 ␤ 1binding motif, GROGER. We used these peptides to investigate, at atomic-level resolution, how these amino acid substitutions affect the collagen III-integrin ␣ 2 ␤ 1 interaction. Using a multitiered approach combining biological adhesion assays, CD, NMR, and molecular dynamics (MD) simulations, we found that these substitutions differentially impede human mesenchymal stem cell spreading and integrin ␣ 2-inserted (␣ 2 I) domain binding to the CMPs and were associated with triple-helix destabilization. Although an Ala substitution locally destabilized hydrogen bonding and enhanced mobility, it did not significantly reduce the CMP-integrin interactions. MD simulations suggested that bulkier Gly 3 Xaa substitutions differentially disrupt the CMP-␣ 2 I interaction. The Gly 3 Arg substitution destabilized CMP-␣ 2 I side-chain interactions, and the Gly 3 Val change broke the essential Mg 2؉ coordination. The relationship between the loss of functional binding and the type of vEDS substitution provides a foundation for developing potential therapies for managing collagen disorders.

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“…This is confirmed by all available structural analysis protein-small molecule interfaces (25). The protein region partially exposed to the solvent lacks large side chains, which is conducive to close contact with small organic molecules, thereby changing or regulating the activity of the protein (26)(27)(28). Given this background, we herein searched the crystal structure of HLA-A*02 restricted antigen peptide-TCR complexes from PDB.…”

Section: Introductionmentioning

confidence: 76%

Characterization of amino acid residues of T-cell receptors interacting with HLA-A*02-restricted antigen peptides

Zhu¹,

Huang²,

Su³

et al. 2021

Ann Transl Med

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Background: The present study aimed to explore residues' properties interacting with HLA-A*02restricted peptides on T-cell receptors (TCRs) and their effects on bond types of interaction and binding free energy.Methods: We searched the crystal structures of HLA-A*02-restricted peptide-TCR complexes from the Protein Data Bank (PDB) database and subsequently collected relevant parameters. We then employed Schrodinger to analyze the bond types of interaction and Gromacs 2019 to evaluate the TCR-antigen peptide complex's molecular dynamics simulation. Finally, we compared the changes of bond types of interaction and binding free energy before and after residue substitution to ensure consistency of the conditions before and after residue substitution. Results:The main sites on the antigen peptides that formed the intermolecular interaction [hydrogen bond (HB) and pi stack] with TCRs were P4, P8, P2, and P6. The hydrophobicity of the amino acids inside or outside the disulfide bond of TCRs may be related to the intermolecular interaction and binding free energy between TCRs and peptides. Residues located outside the disulfide bond of TCR α or β chains and forming pi stack force played favorable roles in the complex intermolecular interaction and binding free energy. The residues of the TCR α or β chains that interacted with peptides were replaced by alanine (Ala) or glycine (Gly), and their intermolecular binding free energy of the complex had been improved. However, it had nothing to do with the formation of HB. Conclusions:The findings of this study suggest that the hydrophobic nature of the amino acids inside or outside the disulfide bonds on the TCR may be associated with the intermolecular interaction and binding between the TCR and polypeptide. The residues located outside the TCR α or β single-chain disulfide bond and forming the pi-stack force showed a beneficial effect on the intermolecular interaction and binding of the complex. In addition, the part of the residues on the TCR α or β single chain that produced bond types of interaction with the polypeptide after being replaced by Ala or Gly, the intermolecular binding free energy of the complex was increased, regardless of whether HB was formed.

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Collagen Gly missense mutations: Effect of residue identity on collagen structure and integrin binding

Cited by 27 publications

References 55 publications

Genotype–Phenotype Association Analysis Reveals New Pathogenic Factors for Osteogenesis Imperfecta Disease

Genotype–Phenotype Association Analysis Reveals New Pathogenic Factors for Osteogenesis Imperfecta Disease

Molecular underpinnings of integrin binding to collagen-mimetic peptides containing vascular Ehlers–Danlos syndrome–associated substitutions

Characterization of amino acid residues of T-cell receptors interacting with HLA-A*02-restricted antigen peptides

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