| Autor: |
Mark S.P. Sansom, Heidi Koldsoe, George Hedger |
| Rok vydání: |
2016 |
| Předmět: |
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| Zdroj: |
Biophysical Journal. 110(3) |
| ISSN: |
0006-3495 |
| DOI: |
10.1016/j.bpj.2015.11.1407 |
| Popis: |
Lipid molecules can bind selectively to specific sites on integral membrane proteins, modulating their function. This includes the epidermal growth factor (EGF) receptor which is known to be modulated by changes in its lipid environment. Mutagenesis studies have previously identified several transmembrane residues critical for lipid sensitivity, suggesting modulation may occur via direct interaction. We have undertaken a series of coarse-grained simulations of the transmembrane helix dimer of the EGF receptor embedded in a lipid bilayer environment. Within equilibrium simulations we observe direct and specific interactions of modulatory lipids with the same residues predicted by mutagenesis studies, as well as a degree of local clustering of modulatory lipids around the receptor as previously observed for monomeric receptor tyrosine kinases. Subsequently we employ potential of mean force (PMF) calculations to compute free energy profiles for these lipids. Interaction free energies ranged from −42 kJ/mol to −4 kJ/mol for different lipid species. Those lipid species known to modulate EGF receptor function exhibit the strongest binding to the receptor, both within the extracellular and intracellular leaflets. Mutation of amino acid residues essential for EGF receptor function severely abrogates binding of key lipids. Our data are supportive of lipid modulation of the EGF receptor via a direct interaction. This approach may provide a generalizable tool for characterizing the interactions of lipids which bind to specific sites on integral membrane proteins. The method is now being applied to probe interactions of cholesterol and other lipids with G-protein coupled receptors (GPCRs). |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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