Growth Factor Identity Is Encoded by Discrete Coiled-Coil Rotamers in the EGFR Juxtamembrane Region

Abstract

Summary Binding of the growth factor TGF-α to the EGFR extracellular domain is encoded through the formation of a unique anti-parallel coiled coil within the juxtamembrane segment. This new coiled coil is an ‘inside-out’ version of the coiled coil formed in the presence of EGF. A third, intermediary coiled coil interface is formed in the juxtamembrane segment when EGFR is stimulated with betacellulin. The seven growth factors that activate EGFR in mammalian systems (EGF, TGF-α, epigen, epiregulin, betacellulin, heparin-binding EGF, and amphiregulin) fall into distinct categories in which the structure of the coiled coil induced within the juxtamembrane segment correlates with cell state. The observation that coiled coil state tracks with the downstream signaling profiles for each ligand provides evidence for growth factor functional selectivity by EGFR. Encoding growth factor identity in alternative coiled coil rotamers provides a simple and elegant method for communicating chemical information across the plasma membrane.

The Membrane Mimetic Affects the Spatial Structure and Mobility of EGFR Transmembrane and Juxtamembrane Domains

“…JMA regions of EGFR are shown to be helical by the number of studies, 4,12,18 and the conformation of the JMA-JMA dimer was even found to be dependent on the type of EGFR ligand. 19 Besides, we suppose that the observed ability of the membrane environment to govern the helicity and membrane binding propensity of the EGFR JMA domains may indicate that cellular membranes can play an active role in the EGFR activation process.…”

EGFR gene deregulation mechanisms in lung adenocarcinoma: A molecular review

“…A variety of extracellular or intracellular ligands of paracrine or autocrine origin -including epidermal growth factor (EGF), transforming growth factor alpha (TGF-a), betacellulin, amphiregulin, epigen, epiregulin and heparin binding EGF-like growth factor-bind to the surface region of the receptor [30]. Ligand binding leads to receptor dimerization due to intermolecular interactions (critical dimerization of domain II with the exception of a truncated sEGFR (sEGFR501) that remain monomeric [31].…”

Dialing in EGFR Signaling

“…Further, it is also unclear how different extracellular growth factors can induce discrete intracellular responses including receptor downregulation versus receptor recycling, all of which are mediated through EGFR signaling. Because EGFR must somehow elicit distinct responses that are contingent upon the extracellular stimuli, Schepartz and colleagues used a clever approach to specifically interrogate changes in the juxtamembrane (JM) region of EGFR in response to various stimuli as a possible mechanism for translating these intracellular messages (Doerner et al, 2015; Figure 1). …”

“…Exactly how ligand binding is translated into specific signaling outcomes remains incompletely understood. In this issue, Doerner et al (2015) provide insights into a role that the juxtamembrane (JM) region of a representative ErbB kinase, EGFR, plays in this process.…”

“…However, because EGFR can bind multiple ligands, it remained unclear what response would be elicited by different growth factors. In the current study, the authors comprehensively investigated JM-A conformations following stimulation using seven distinct growth factors (Doerner et al, 2015). In addition, they used multiple tetracysteine mutants of EGFR so as to probe all possible PPI interfaces that could be formed by JM-A dimers.…”