Lipid-Protein Interplay in Dimerization of Juxtamembrane Domains of Epidermal Growth Factor Receptor

Biophysical Journal
Ryo MaedaYasushi Sako

Abstract

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. In particular, 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 the monomer (inactive state)-to-dimer (active state) transition of JM domains and alteration in the pathways depending on the membrane lipid species and Thr654 ...Continue Reading

Citations

Sep 25, 2019·Biomolecules·Louise Conrard, Donatienne Tyteca
Dec 6, 2019·Journal of Computational Chemistry·Daisuke MatsuokaYuji Sugita
Jan 29, 2021·The Journal of Membrane Biology·Aiswarya B Pawar, Durba Sengupta
Nov 7, 2020·Biochemical Society Transactions·Jasmine CornishHelen R Mott
May 3, 2021·Biochimica Et Biophysica Acta. Biomembranes·Mikito NakanoMichio Murata
Jul 10, 2021·Progress in Lipid Research·Do-Hyeon KimSung Ho Ryu
Aug 5, 2021·Biochemical Society Transactions·Alyssa E WardFrancisco N Barrera

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