Mechanism of Allosteric Coupling into and through the Plasma Membrane by EGFR

Abstract

Epidermal growth factor receptor (EGFR) interacts through its extracellular domain with seven different growth factors. These factors induce different structures within the cytoplasmic juxtamembrane (JM) segment of the dimeric receptor and propagate different growth factor-dependent signals to the cell interior. How this process occurs is unknown. Here we apply diverse experimental and computational tools to show that growth factor identity is encoded by the EGFR transmembrane (TM) helix into discrete helix dimer populations that differ in both cross-location and cross-angle. Helix dimers with smaller cross-angles at multiple cross locations are decoded to induce an EGF-type coiled coil in the adjacent JM, whereas helix dimers with larger cross-angles at fewer cross locations induce the TGF-α-type coiled coil. We propose an updated model for how conformational coupling across multiple EGFR domains results in growth factor-specific information transfer, and demonstrate that this model applies to both EGFR and the related receptor ErbB2.

Unique transmembrane domain interactions differentially modulate integrin αvβ3 and αIIbβ3 function

“…Often the TM helices contain two TM-helix interaction motifs, arranged such that both motifs cannot simultaneously engage a single target without large structural distortions. At the outset of our investigation, we expected that the different helix-helix interaction motifs might be alternatively engaged during the dynamics of signaling, as has been proposed for members of the EGF receptor family (37,38). Therefore, we were surprised to find that the two motifs found in the β3 TM helix mediate interactions with two different α-subunits.…”

Antidepressant drugs act by directly binding to TRKB neurotrophin receptors

“…Simulation of TRKB dimerization at transmembrane (TM) helices disclosed five possible structures, but only a cross-like conformation, crossing at the A443-G439 motif, was stable in phosphatidylcholine bilayer with 0 or 20mol% cholesterol ( figure 3A,B) ( 30 ) . The Y433 residue (located within CARC motif) stabilizes the structure, and Y433F destabilized it by rotating the TM monomers 40 degrees relative to each other ( figure 3D).…”

The multifunctional role of phospho-calmodulin in pathophysiological processes

“…This indeed was the case [18,19], and the site of interaction of phospho-Tyr-CaM with the receptor was stablished to be the same that the one for non-phosphorylated CaM located at the cytosolic juxtamembrane region encompassing the sequence 645 RRRHIVRKRTLRRLLQ 660 [19]. The NMR-derived structure of a peptide corresponding to the transmembrane (TM) and the cytosolic juxtamembrane (JM cyt ) segment, where the CaM-BD is located, reconstituted in lipid bicelles shows that they form dimers and that the CaM-BD presents two helical segments divided by a flexible linker [20,21] (see Figure 2). This flexible linker is important to understand the expected bending of the JM cyt to facilitate electrostatic interaction with the phosphoinositide-rich negatively charged inner leaflet of the plasma membrane to attain auto-inhibition of the EGFR in the absence of ligand [22].…”