期刊
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
卷 1850, 期 5, 页码 1017-1025出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbagen.2014.09.006
关键词
EGFR; Juxtamembrane domain; PIP2; Molecular dynamics; Lipid bilayer
资金
- BBSRC [BB/G006911/1]
- Wellcome Trust [WT092970MA]
- Yayasan Khazanah-OCIS Merdeka Scholarship Program
- Biotechnology and Biological Sciences Research Council [BB/G006911/1] Funding Source: researchfish
- BBSRC [BB/G006911/1] Funding Source: UKRI
Background: The epidermal growth factor receptor (EGFR) is the best characterised member of the receptor tyrosine kinases, which play an important role in signalling across mammalian cell membranes. The EGFR juxtamembrane (JM) domain is involved in the mechanism of activation of the receptor, interacting with the anionic lipid phosphatidylinositol 4,5-bisphosphate (PIP2) in the intracellular leaflet of the cell membrane. Methods: Multiscale MD simulations were used to characterize PIP2-JM interactions. Simulations of the transmembrane helix plus JM region (TM-JM) dimer (PDB:2M20) in both PIP2-containing and PIP2-depleted lipid bilayer membranes revealed the interactions of the JM with PIP2 and other lipids. Results: PIP2 forms strong interactions with the basic residues in the R645-R647 motif of the JM domain resulting in clustering of PIP2 around the protein. This association of PIP2 and the JM domain aids stabilization of JM-A dimer away from the membrane. Mutation (R645N/R646N/R647N) or PIP2-depletion results in deformation of the JM-A dimer and changes in JM-membrane interactions. Conclusions: These simulations support the proposal that the positively charged residues at the start of the JM-A domain stabilize the JM-A helices in an orientation away from the membrane surface through binding to PIP2, thus promoting a conformation corresponding to an asymmetric (i.e. activated) kinase. General significance: This study indicates that MD simulations may be used to characterise JM/lipid interactions, thus helping to define their role in the mechanisms of receptor tyrosine kinases. This article is part of a Special Issue entitled Recent developments of molecular dynamics. (C) 2014 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).
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