scholarly journals Lipid-protein interplay in dimerization of the juxtamembrane domains of epidermal growth factor receptor

2017 ◽  
Author(s):  
Ryo Maeda ◽  
Takeshi Sato ◽  
Kenji Okamoto ◽  
Masataka Yanagawa ◽  
Yasushi Sako
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Single Molecule ◽  
Membrane Lipids ◽  
Growth Factor Receptor ◽  
Single Pair ◽  
Lipid Species ◽  
Epidermal Growth ◽  
Acidic Lipids

AbstractTransmembrane (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. Especially, 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 monomer (inactive state) - dimer (active state) transition of JM domains and alteration in the pathways depending on the membrane lipid species and Thr654 phosphorylation.

scholarly journals Single-Molecule Investigation of Conformational Changes in Epidermal Growth Factor Receptor

2020 ◽  
Vol 118 (3) ◽  
pp. 188a
Author(s):  
Raju Regmi ◽  
Shwetha Srinivasan ◽  
Xingcheng Lin ◽  
Steven Quinn ◽  
Wei He ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Single Molecule ◽  
Conformational Changes ◽  
Growth Factor Receptor ◽  
Epidermal Growth

scholarly journals Single molecule analysis of signal transduction through epidermal growth factor receptor

2001 ◽  
Vol 41 (supplement) ◽  
pp. S29
Author(s):  
M. Morimatsu ◽  
K. Ota ◽  
K. Hibino ◽  
T. Miyauchi ◽  
T. Uyemura ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Single Molecule ◽  
Growth Factor Receptor ◽  
Epidermal Growth ◽  
Single Molecule Analysis

scholarly journals Molecular basis for multimerization in the activation of the epidermal growth factor receptor

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Yongjian Huang ◽  
Shashank Bharill ◽  
Deepti Karandur ◽  
Sean M Peterson ◽  
Morgan Marita ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Single Molecule ◽  
Structural Model ◽  
Growth Factor Receptor ◽  
Phosphatidyl Inositol ◽  
Kinase Domain ◽  
Epidermal Growth ◽  
Self Association

The epidermal growth factor receptor (EGFR) is activated by dimerization, but activation also generates higher-order multimers, whose nature and function are poorly understood. We have characterized ligand-induced dimerization and multimerization of EGFR using single-molecule analysis, and show that multimerization can be blocked by mutations in a specific region of Domain IV of the extracellular module. These mutations reduce autophosphorylation of the C-terminal tail of EGFR and attenuate phosphorylation of phosphatidyl inositol 3-kinase, which is recruited by EGFR. The catalytic activity of EGFR is switched on through allosteric activation of one kinase domain by another, and we show that if this is restricted to dimers, then sites in the tail that are proximal to the kinase domain are phosphorylated in only one subunit. We propose a structural model for EGFR multimerization through self-association of ligand-bound dimers, in which the majority of kinase domains are activated cooperatively, thereby boosting tail phosphorylation.

scholarly journals Single-Molecule Fluorescence Detection of the Epidermal Growth Factor Receptor in Membrane Discs

Biochemistry ◽  
2018 ◽  
Vol 58 (4) ◽  
pp. 286-294 ◽  
Author(s):  
Steven D. Quinn ◽  
Shwetha Srinivasan ◽  
Jesse B. Gordon ◽  
Wei He ◽  
Kermit L. Carraway ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Fluorescence Detection ◽  
Single Molecule ◽  
Growth Factor Receptor ◽  
Single Molecule Fluorescence ◽  
Epidermal Growth

Structure–function relationships and supramolecular organization of the EGFR (epidermal growth factor receptor) on the cell surface

2014 ◽  
Vol 42 (1) ◽  
pp. 114-119 ◽  
Author(s):  
Sarah R. Needham ◽  
Laura C. Zanetti-Domingues ◽  
Michael Hirsch ◽  
Daniel J. Rolfe ◽  
Christopher J. Tynan ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Single Molecule ◽  
Growth Factor Receptor ◽  
Supramolecular Organization ◽  
Cortical Actin ◽  
Current State ◽  
Epidermal Growth ◽  
In Cells

Dimerization and higher-order oligomerization are believed to play an important role in the activation of the EGFR (epidermal growth factor receptor). Understanding of the process has been limited by the lack of availability of suitable methods for the measurement in cells of distances in the range 10–100 nm, too short for imaging methods and too long for spectroscopic methods such as FRET. In the present article, we review the current state of our knowledge of EGFR oligomerization, and describe results from a new single-molecule localization method that has allowed the quantitative characterization of the distribution of EGFR–EGFR distances in cells. Recent data suggest the involvement of cortical actin in regulating the formation of EGFR complexes.

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