Ligands with different dimeric configurations potently activate the EphA2 receptor and reveal its potential for biased signaling

Gómez-Soler, Maricel; Gehring, Marina P.; Lechtenberg, Bernhard C.; Zapata-Mercado, Elmer; Ruelos, Alyssa; Matsumoto, Mike W.; Hristova, Kalina; Pasquale, Elena B.

doi:10.1016/j.isci.2022.103870

Cited by 18 publications

(59 citation statements)

References 102 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Experiments to compare EphA2 wild-type with the HR and GZ mutants were performed in the absence of ligand as well as in the presence of saturating/near saturating concentrations of ephrinA1-Fc (50 nM), m-ephrinA1 (200 nM) or YSA peptide (50 μM) (40) to ensure that most EphA2 receptors were ligand bound, and therefore that essentially only liganded dimers/oligomers contributed to the FRET signal. Figure 1 shows the measured FRET efficiencies as a function of donor (EphA2-mTurq), acceptor (EphA2-eYFP), and total receptor concentrations, with each data point corresponding to one cell.…”

Section: Resultsmentioning

confidence: 99%

“…We also found that ligands do not always cause substantial EphA2 activation. For instance, the small monomeric peptide ligand YSA-GSGSK (YSAYPDSVPMMSGSGSK) activates EphA2 only very weakly (40,44). Although the three ligands can stabilize different EphA2 oligomeric assemblies in the plasma membrane of live cells (45), it is not known whether the TM helix plays a role in these assemblies.…”

Section: Introductionmentioning

confidence: 99%

“…Other recent findings further raise the possibility that the specific arrangement of the TM helices in EphA2 dimers and oligomers may not be critical for receptor activation. For instance, deletion of most of the juxtamembrane segment (residues 565 to 606) severely compromises the ability of EphA2 molecules to cross-phosphorylate on the remaining tyrosine residues (including Y772 in the activation loop of the kinase domain and Y930 in the SAM domain) (40). This suggests that the flexible juxtamembrane sequence, connecting the TM helix with the kinase domain, allows differential positioning of EphA2 molecules for cross-phosphorylation on different tyrosine residues.…”

Section: Introductionmentioning

confidence: 99%

“…EphrinA1-Fc potently promotes EphA2 kinase-dependent signaling (34,42). The endogenous form of ephrinA1 is anchored on the cell surface by a glycosylphosphatidylinositol (GPI) linkage, but can also be released in a monomeric form (m-ephrinA1) that can also activate EphA2 (40,43). We recently found that these are biased ligands (40).…”

Section: Introductionmentioning

confidence: 99%

“…The endogenous form of ephrinA1 is anchored on the cell surface by a glycosylphosphatidylinositol (GPI) linkage, but can also be released in a monomeric form (m-ephrinA1) that can also activate EphA2 (40,43). We recently found that these are biased ligands (40). We also found that ligands do not always cause substantial EphA2 activation.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Plasticity of transmembrane helix interactions in EphA2 dimers and oligomers

Wirth

Özdemir

Wimley

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Lateral interactions can stabilize different EphA2 receptor assemblies in the plasma membrane in response to different ligands. Here we use two fluorescent techniques, Forster Resonance Energy Transfer (FRET) and Fluorescence Intensity Fluctuations (FIF) spectrometry, to investigate how mutations in the EphA2 transmembrane (TM) helix affect the association between full-length EphA2 molecules in the absence of ligand and in the presence of three ligands: ephrinA1-Fc, m-ephrinA1, and the YSA peptide. The EphA2 mutations we studied have been previously characterized in the context of the isolated EphA2 TM helix. Working with full-length EphA2, we observed modest effects of the mutations on receptor-receptor interaction. Our data do not support the currently accepted model of a switch between two discrete TM helix dimerization motifs corresponding to active or inactive receptor states. Instead, we propose that different dimeric/oligomeric arrangements of the EphA2 extracellular region couple to an ensemble of TM helix dimer interfaces. Plasticity in the arrangements of receptor tyrosine kinase TM helices in active dimers and oligomers may serve to facilitate the cross phosphorylation of multiple tyrosines in different positions of the intracellular regions.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Plasticity of transmembrane helix interactions in EphA2 dimers and oligomers

Wirth

Özdemir

Wimley

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

2‐Pyridone Formation: An Efficient Method for the Solid‐Phase Synthesis of Homodimers

Abboud,

Kodadek

2023

Chemistry A European J

View full text Add to dashboard Cite

This study presents an efficient method for on‐resin dimer generation through self‐condensation of 3,3‐dimethoxypropionic acid‐modified molecules, resulting in 2‐pyridones. The approach demonstrated remarkable versatility by producing homodimers of peptides, peptoids, and non‐peptidic ligands. Its ease of application, broad utility, and mild reaction conditions not only hold significance for peptide and peptoid research but also offer potential for the on‐resin development of a wide range of bivalent ligands.

show abstract