Structural determinants for membrane binding of the EGFR juxtamembrane domain

The region containing residues I649  − L659 of the epidermal growth factor receptor (EGFR) juxtamembrane domain (JM) specifically interacts with PI(4,5)P2-or phosphatidylserine-containing membranes, suggesting that membrane binding may affect JM dimerization and, therefore, regulate EGFR kinase activation. 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)P2-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,655LRRLL659, suggesting that membrane binding may affect JM dimerization and, therefore, regulate kinase activation.
Source: FEBS Letters - Category: Biochemistry Authors: Tags: Research Letter Source Type: research