title: The Conformation of the Epidermal Growth Factor Receptor Transmembrane Domain Dimer Dynamically Adapts to the Local Membrane Environment.
abstract: The epidermal growth factor receptor (EGFR) family is an important class of receptor tyrosine kinases, mediating a variety of cellular responses in normal biological processes and in pathological states of multicellular organisms. Different modes of dimerization of the human EGFR transmembrane domain (TMD) in different membrane mimetics recently prompted us to propose a novel signal transduction mechanism based on protein-lipid interaction. However, the experimental evidence for it was originally obtained with slightly different TMD fragments used in the two different mimetics, compromising the validity of the comparison. To eliminate ambiguity, we determined the nuclear magnetic resonance (NMR) structure of the bicelle-incorporated dimer of the EGFR TMD fragment identical to the one previously used in micelles. The NMR results augmented by molecular dynamics simulations confirm the mutual influence of the TMD and lipid environment, as is required for the proposed lipid-mediated activation mechanism. They also reveal the possible functional relevance of a subtle interplay between the concurrent processes in the lipid and protein during signal transduction.
authors.affiliation: Department of Structural Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS , str. Miklukho-Maklaya 16/10, Moscow 117997, Russian Federation.
authors.forename: Eduard V
authors.identifier: 0000-0002-3635-1609
authors.initials: EV
authors.lastname: Bocharov
authors.affiliation: Department of Structural Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS , str. Miklukho-Maklaya 16/10, Moscow 117997, Russian Federation.
authors.forename: Pavel E
authors.initials: PE
authors.lastname: Bragin
authors.affiliation: Department of Structural Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS , str. Miklukho-Maklaya 16/10, Moscow 117997, Russian Federation.
authors.forename: Konstantin V
authors.initials: KV
authors.lastname: Pavlov
authors.affiliation: Department of Structural Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS , str. Miklukho-Maklaya 16/10, Moscow 117997, Russian Federation.
authors.forename: Olga V
authors.initials: OV
authors.lastname: Bocharova
authors.affiliation: Department of Structural Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS , str. Miklukho-Maklaya 16/10, Moscow 117997, Russian Federation.
authors.forename: Konstantin S
authors.initials: KS
authors.lastname: Mineev
authors.affiliation: Department of Structural Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS , str. Miklukho-Maklaya 16/10, Moscow 117997, Russian Federation.|Department of Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna , Campus Vienna Biocenter 5, Vienna AT-1030, Austria.
authors.forename: Anton A
authors.identifier: 0000-0002-1011-2706
authors.initials: AA
authors.lastname: Polyansky
authors.affiliation: Department of Structural Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS , str. Miklukho-Maklaya 16/10, Moscow 117997, Russian Federation.
authors.forename: Pavel E
authors.initials: PE
authors.lastname: Volynsky
authors.affiliation: Department of Structural Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS , str. Miklukho-Maklaya 16/10, Moscow 117997, Russian Federation.|Higher School of Economics , Myasnitskaya ul. 20, Moscow 101000, Russian Federation.
authors.forename: Roman G
authors.initials: RG
authors.lastname: Efremov
authors.affiliation: Department of Structural Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS , str. Miklukho-Maklaya 16/10, Moscow 117997, Russian Federation.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Arseniev
mesh_terms: D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000737:chemistry* / Q000378:metabolism; D003001:Cloning, Molecular; D004134:Dimyristoylphosphatidylcholine / Q000737:chemistry / Q000378:metabolism; D066246:ErbB Receptors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism; D008823:Micelles; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010742:Phospholipid Ethers / Q000737:chemistry / Q000378:metabolism; D000072417:Protein Domains; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*
chemical_list: C052298:1,2-dihexadecyl-sn-glycero-3-phosphocholine; D008051:Lipid Bilayers; D008823:Micelles; D010455:Peptides; D010742:Phospholipid Ethers; D011994:Recombinant Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; D004134:Dimyristoylphosphatidylcholine