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Structural determinants for membrane binding of the EGFR juxtamembrane domain.

Ziwei WuLing LiLina ZhuRunhan WangYingkui DongYaoyao ZhangYujuan WangJunfeng WangLei Zhu
Published in: FEBS letters (2024)
Overactivation of the epidermal growth factor receptor (EGFR) is critical for the development of multiple cancers. Previous studies have shown that the cell membrane is a key regulator of EGFR kinase activity through its interaction with the EGFR juxtamembrane domain (JM). However, the lipid recognition specificity of EGFR-JM and its interaction details remain unclear. Using lipid strip and liposome pulldown assays, we showed that EGFR-JM could specifically interact with PI(4,5)P 2 -or phosphatidylserine-containing membranes. We further characterized the JM-membrane interaction using NMR-titration-based chemical shift perturbation and paramagnetic relaxation enhancement analyses, and found that residues I649 - L659 comprised the membrane-binding site. Furthermore, the membrane-binding region contains the predicted dimerization motif of JM, 655 LRRLL 659 , suggesting that membrane binding may affect JM dimerization and, therefore, regulate kinase activation.
Keyphrases
  • epidermal growth factor receptor
  • tyrosine kinase
  • small cell lung cancer
  • advanced non small cell lung cancer
  • high resolution
  • magnetic resonance
  • binding protein
  • dna binding
  • protein kinase
  • single cell