4.8 Article

N-Glycosylation as determinant of epidermal growth factor receptor conformation in membranes

出版社

NATL ACAD SCIENCES
DOI: 10.1073/pnas.1503262112

关键词

EGFR; lipids; MD simulation; lipid-protein interaction; proteoliposomes

资金

  1. Academy of Finland [Center of Excellence scheme]
  2. European Research Council [Advanced Grant CROWDED-PRO-LIPIDS]
  3. Sigrid Juselius Foundation
  4. Deutsche Forschungsgemeinschaft Transregio 83 Grant [TRR83 TP18]
  5. German Federal Ministry of Education and Research grant

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The epidermal growth factor receptor (EGFR) regulates several critical cellular processes and is an important target for cancer therapy. In lieu of a crystallographic structure of the complete receptor, atomistic molecular dynamics (MD) simulations have recently shown that they can excel in studies of the full-length receptor. Here we present atomistic MD simulations of the monomeric N-glycosylated human EGFR in biomimetic lipid bilayers that are, in parallel, also used for the reconstitution of full-length receptors. This combination enabled us to experimentally validate our simulations, using ligand binding assays and antibodies to monitor the conformational properties of the receptor reconstituted into membranes. We find that N-glycosylation is a critical determinant of EGFR conformation, and specifically the orientation of the EGFR ectodomain relative to the membrane. In the absence of a structure for full-length, posttranslationally modified membrane receptors, our approach offers new means to structurally define and experimentally validate functional properties of cell surface receptors in biomimetic membrane environments.

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