Plasticity of transmembrane helix interactions in EphA2 dimers and oligomers

Wirth, D.; Ozdemir, E.; Wimley, W. C.; Pasquale, E. B.; Hristova, K.

doi:10.1101/2022.06.06.495010

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bioRxiv · 10.1101/2022.06.06.495010

Plasticity of transmembrane helix interactions in EphA2 dimers and oligomers

Wirth, D.·Ozdemir, E.·Wimley, W. C.·Pasquale, E. B.·Hristova, K.

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Abstract

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.

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Wirth, D., Ozdemir, E., Wimley, W. C., Pasquale, E. B., Hristova, K.. 2022-06-06. Plasticity of transmembrane helix interactions in EphA2 dimers and oligomers. https://doi.org/10.1101/2022.06.06.495010

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