Correlation between experimentally indicated and atomistically simulated roles of EGFR N-glycosylation

Irani, Maryam Azimzadeh

doi:10.1080/08927022.2018.1447108

Cited by 10 publications

(5 citation statements)

References 38 publications

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“…The average RMSD values also show that the gmRBDfN system is the most stable. This observation was expected as several other experimental, computational, and structural studies have reported that glycosylation contributes to increasing the stability of protein structures ( Solá and Griebenow, 2009 ; Azimzadeh Irani, 2018 ; Azimzadeh Irani and Ejtehadi, 2019 ; Motamedi et al, 2021 ).…”

Section: Resultssupporting

confidence: 80%

“…Glycosylation is the most common posttranslational modification that occurs for the virus, and the SARS-CoV-2 proteins, especially the S protein and its receptor ACE2, are densely glycosylated ( Shajahan et al, 2020 ; Woo et al, 2020 ; Gong et al, 2021 ; Guo et al, 2021 ). In several studies, glycosylation has been shown to be essential for protein folding, stability, and ligand binding ( Azimzadeh Irani et al, 2017 ; Azimzadeh Irani, 2018 ; Azimzadeh Irani and Ejtehadi, 2020 ; Motamedi et al, 2021 ; Rahnama et al, 2021 ). Both N-glycosylation and O-glycosylation occur on the spike protein of SARS-CoV-2, and the latter has a significant effect on virus function and infectivity ( Xu et al, 2020 ; Yasunori et al, 2020 ; Antonopoulos et al, 2021 ; Bagdonaite et al, 2021 ; Reis et al, 2021 ; Zhang et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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In silico design of refined ferritin-SARS-CoV-2 glyco-RBD nanoparticle vaccine

Nomandan

Irani

Hosseini

2022

Front. Mol. Biosci.

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With the onset of Coronavirus disease 2019 (COVID-19) pandemic, all attention was drawn to finding solutions to cure the coronavirus disease. Among all vaccination strategies, the nanoparticle vaccine has been shown to stimulate the immune system and provide optimal immunity to the virus in a single dose. Ferritin is a reliable self-assembled nanoparticle platform for vaccine production that has already been used in experimental studies. Furthermore, glycosylation plays a crucial role in the design of antibodies and vaccines and is an essential element in developing effective subunit vaccines. In this computational study, ferritin nanoparticles and glycosylation, which are two unique facets of vaccine design, were used to model improved nanoparticle vaccines for the first time. In this regard, molecular modeling and molecular dynamics simulation were carried out to construct three atomistic models of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domain (RBD)-ferritin nanoparticle vaccine, including unglycosylated, glycosylated, and modified with additional O-glycans at the ferritin–RBD interface. It was shown that the ferritin–RBD complex becomes more stable when glycans are added to the ferritin–RBD interface and optimal performance of this nanoparticle can be achieved. If validated experimentally, these findings could improve the design of nanoparticles against all microbial infections.

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Section: Resultssupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

In silico design of refined ferritin-SARS-CoV-2 glyco-RBD nanoparticle vaccine

Nomandan

Irani

Hosseini

2022

Front. Mol. Biosci.

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“…The locations of glycosylated Asparagine residues are shown, one highlighted inside a grey box. Taken, with permission, from Irani [93]. ( e ) A molecular dynamic (MD) simulation of the sEGFR started from the structure in d. The connecting point between the extracellular and the transmembrane helices is marked by a circle.…”

Section: Figurementioning

confidence: 99%

Structure and Dynamics of the EGF Receptor as Revealed by Experiments and Simulations and Its Relevance to Non-Small Cell Lung Cancer

Martin-Fernandez

Clarke

Roberts

et al. 2019

Cells

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The epidermal growth factor receptor (EGFR) is historically the prototypical receptor tyrosine kinase, being the first cloned and the first where the importance of ligand-induced dimer activation was ascertained. However, many years of structure determination has shown that EGFR is not completely understood. One challenge is that the many structure fragments stored at the PDB only provide a partial view because full-length proteins are flexible entities and dynamics play a key role in their functionality. Another challenge is the shortage of high-resolution data on functionally important higher-order complexes. Still, the interest in the structure/function relationships of EGFR remains unabated because of the crucial role played by oncogenic EGFR mutants in driving non-small cell lung cancer (NSCLC). Despite targeted therapies against EGFR setting a milestone in the treatment of this disease, ubiquitous drug resistance inevitably emerges after one year or so of treatment. The magnitude of the challenge has inspired novel strategies. Among these, the combination of multi-disciplinary experiments and molecular dynamic (MD) simulations have been pivotal in revealing the basic nature of EGFR monomers, dimers and multimers, and the structure-function relationships that underpin the mechanisms by which EGFR dysregulation contributes to the onset of NSCLC and resistance to treatment.

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“…38 Molecular dynamic simulations of glycosylation at N361 of EGFR showed large changes in side-chains, differences which were magnified in the presence of EGF ligand. 25,26,41,42 These simulations also suggested that glycosylation sugars at N361 may interact with the opposing EGFR dimer. 25,36 However, the functional relevance of how glycosylation of EGFR at N361 impacts EGFR protein and cellular behaviors remains unclear.…”

Section: Introductionmentioning

confidence: 80%

Effects of N361 Glycosylation on Epidermal Growth Factor Receptor Biological Function

Lam,

Arroyo,

Liberchuk

et al. 2024

Preprint

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Epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase that is frequently modified by glycosylation post-translationally. In cancer, EGFR amplifications and hotspot mutations such as L858R that promote proliferation have been detected in a significant fraction of non-small cell lung carcinomas and breast adenocarcinomas. Molecular dynamic simulations suggested that glycosylation at asparagine residue 361 (N361) promotes dimerization and ligand binding. We stably expressed glycosylation-deficient mutant EGFR N361A, with or without the oncogenic mutation L858R. Immunofluorescence and flow cytometry demonstrated that the mutants were each well expressed at the cell membrane. N361A decreased proliferation relative to wild-type EGFR as well as decreased sensitivity to ligands. Proximity ligation assays measuring co-localization of EGFR with its binding partner HER2 in cells revealed that N361A mutations increased co-localization. N361A, located near the binding interface for the EGFR inhibitor necitumumab, desensitized cells expressing the oncogenic EGFR L858R to antibody-based inhibition. These findings underline the critical relevance of post-translational modifications on oncogene function.SIGNIFICANCEEGFR transduces signals from growth factors into cell proliferation and is frequently hyperactivated in tumors. Glycosylation of EGFR at N361 regulates EGFR dimerization, growth factor stimulation of proliferative signaling, and susceptibility to targeted inhibition. Insights into EGFR glycosylation may expand therapeutic opportunities to benefit cancer patients.

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Correlation between experimentally indicated and atomistically simulated roles of EGFR N-glycosylation

Cited by 10 publications

References 38 publications

In silico design of refined ferritin-SARS-CoV-2 glyco-RBD nanoparticle vaccine

In silico design of refined ferritin-SARS-CoV-2 glyco-RBD nanoparticle vaccine

Structure and Dynamics of the EGF Receptor as Revealed by Experiments and Simulations and Its Relevance to Non-Small Cell Lung Cancer

Effects of N361 Glycosylation on Epidermal Growth Factor Receptor Biological Function

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