Conformational Changes in the Epidermal Growth Factor Receptor: Role of the Transmembrane Domain Investigated by Coarse-Grained MetaDynamics Free Energy Calculations

Lelimousin, Mickaël; Limongelli, Vittorio; Sansom, Mark S. P.

doi:10.1021/jacs.6b05602

Cited by 110 publications

(143 citation statements)

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“…Such methods, which are routinely used elsewhere, can push the boundaries of biochemical investigations of membrane proteins. [51][52][53] Therefore, insights gained from this work will potentially guide future experiments to unravel the complexities of blood-brain barrier TJs.…”

Section: Discussionmentioning

confidence: 93%

“…The state‐of‐the‐art methods used in this study are robust and were able to capture the specificity of single‐residue mutations. Such methods, which are routinely used elsewhere, can push the boundaries of biochemical investigations of membrane proteins . Therefore, insights gained from this work will potentially guide future experiments to unravel the complexities of blood–brain barrier TJs.…”

Section: Discussionmentioning

confidence: 99%

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Architecture of the paracellular channels formed by claudins of the blood–brain barrier tight junctions

Irudayanathan

Wang

et al. 2017

Annals of the New York Academy of Sciences

120

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Tight junctions (TJs) are key players in determining tissue-specific paracellular permeability across epithelial and endothelial membranes. Claudin proteins, the primary determinants of TJs structure and functionality, assemble in paracellular spaces to form channels and pores that are charge and size selective. Here, using molecular dynamics (MD) simulations, we elucidate the molecular assembly of claudin-3 and claudin-5 proteins of blood-brain barrier TJs. Despite having a high degree of sequence and structural similarity, these two claudins form different types of cis-interactions. Molecular docking of the observed cis-interfaces into trans-forms revealed two putative pore models that were also observed in the self-assembly simulations. The observed pore structures (pore I and II) have pore-lining residues that have been previously reported in the literature. The pore I model is consistent with a previously reported claudin-15 model. The pore II model, also consistent with biochemical results, has not been reported previously. Further analysis using in silico site-directed mutations provide convincing support for the validity of the pore II model. Using steered MD and umbrella sampling, we computed the transport properties of water and α-d-glucose through pore II. The study offers new insight into the selectivity of blood-brain barrier TJs.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Architecture of the paracellular channels formed by claudins of the blood–brain barrier tight junctions

Irudayanathan

Wang

et al. 2017

Annals of the New York Academy of Sciences

120

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“…The Martini force field developed by Marrink and coworkers is perhaps the most widely used model for CG simulations of biological membranes. Some examples of recent successes are combination of the force field with the metadynamics method of enhanced sampling to study the energetics of conformational rearrangements in the epidermal growth factor receptor; high throughput simulations showing the effects of alcohol on a mechanosensitive protein; studies of local phase transitions in bacterial membranes induced by an antimicrobial peptide; and unraveling of the plastoquinone exchange pathways of the photosystem II complex . A key advantage of CG models is the ability to self‐assemble the lipid component whether this be a flat bilayer, a micelle, or a small spherical vesicle in the presence or absence of proteins of interest, thereby eliminating the initial “guesswork” of determining how proteins are oriented and packed by the lipids and/or detergents in each environment.…”

Section: Introductionmentioning

confidence: 99%

CHARMM‐GUI Martini Maker for modeling and simulation of complex bacterial membranes with lipopolysaccharides

et al. 2017

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A complex cell envelope, composed of a mixture of lipid types including complex lipopolysaccharides, protects bacteria from the external environment. Clearly, the proteins embedded within the various components of the cell envelope have an intricate relationship with their local environment. Therefore, to obtain meaningful results, molecular simulations need to mimic as far as possible this chemically heterogeneous system. However, setting up such systems for computational studies is far from trivial, and consequently the vast majority of simulations of outer membrane proteins still rely on oversimplified phospholipid membrane models. This work presents an update of CHARMM-GUI Martini Maker for coarse-grained modeling and simulation of complex bacterial membranes with lipopolysaccharides. The qualities of the outer membrane systems generated by Martini Maker are validated by simulating them in bilayer, vesicle, nanodisc, and micelle environments (with and without outer membrane proteins) using the Martini force field. We expect this new feature in Martini Maker to be a useful tool for modeling large, complicated bacterial outer membrane systems in a user-friendly manner.

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“…domains 9,13,14 . This information regarding conformational changes in the TM dimer is transmitted to the JM domains.…”

mentioning

confidence: 99%

Lipid-protein interplay in dimerization of the juxtamembrane domains of epidermal growth factor receptor

Maeda

Sato

Okamoto

et al. 2017

Preprint

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Transmembrane (TM) helix and juxtamembrane (JM) domains (TM-JM) bridge the extracellular and intracellular domains of single-pass membrane proteins, including epidermal growth factor receptor (EGFR). TM-JM dimerization plays a crucial role in regulation of EGFR kinase activity at the cytoplasmic side. Although the interaction of JM with membrane lipids is thought to be important to turn on EGF signaling and phosphorylation of Thr654 on JM leads to desensitization, the underlying kinetic mechanisms remain unclear. Especially, how Thr654 phosphorylation regulates EGFR activity is largely unknown. Here, combining single-pair FRET imaging and nanodisc techniques, we showed that phosphatidylinositol 4,5-bis phosphate (PIP2) facilitated JM dimerization effectively. We also found that Thr654 phosphorylation dissociated JM dimers in the membranes containing acidic lipids, suggesting that Thr654 phosphorylation electrostatically prevented the interaction with basic residues in JM and acidic lipids. Based on the single-molecule experiment, we clarified the kinetic pathways of monomer (inactive state) -dimer (active state) transition of JM domains and alteration in the pathways depending on the membrane lipid species and Thr654 phosphorylation.. CC-BY-NC-ND 4.0 International license not peer-reviewed) is the author/funder. It is made available under aThe copyright holder for this preprint (which was . http://dx.doi.org/10.1101/197673 doi: bioRxiv preprint first posted online Oct. 19, 2017; 3 Epidermal growth factor receptor (EGFR), the best studied receptor tyrosine kinase (RTK), plays an important role in regulating cell proliferation and differentiation 1,2 .EGFR consists of an extracellular domain that interacts with extracellular ligands, a single-pass transmembrane (TM) helix, a juxtamembrane (JM) domain, a cytoplasmic kinase domain that activates various signal cascades in the cell, and a C-terminal tail domain 3,4 . When ligands such as EGF bind to the extracellular domain of EGFR, conformational changes occur in the extracellular domain and the asymmetric dimer of intracellular kinase domains is formed 5 . This asymmetric dimerization enables one (activator) kinase domain to activate the other (receiver) kinase domain 6 , resulting in subsequent phosphorylation of tyrosine residues on the C-terminal tails of the activator and recruitment of intracellular signal proteins containing an SH2 and/or PTB domain, such as Shc, Grb2, etc. 7 .Although the structures of most of the EGFR domains excluding the C-tail domain 5,6,[8][9][10] have been solved individually, the overall architecture remains unclear. In particular, the most important question regarding the regulation of EGFR kinase activity across the lipid bilayer, i.e., the correlation between conformational changes in the extracellular domain upon ligand binding and rearrangement of the intracellular kinase domain, is still controversial.In the context of transmission of information across the membrane, the single-pass TM helix and the JM domain (TM-JM...

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Conformational Changes in the Epidermal Growth Factor Receptor: Role of the Transmembrane Domain Investigated by Coarse-Grained MetaDynamics Free Energy Calculations

Cited by 110 publications

References 106 publications

Architecture of the paracellular channels formed by claudins of the blood–brain barrier tight junctions

Architecture of the paracellular channels formed by claudins of the blood–brain barrier tight junctions

CHARMM‐GUI Martini Maker for modeling and simulation of complex bacterial membranes with lipopolysaccharides

Lipid-protein interplay in dimerization of the juxtamembrane domains of epidermal growth factor receptor

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