Abstract
The epidermal growth factor receptor (EGFR) is a dimeric membrane protein that regulates key aspects of cellular function. Activation of the EGFR is linked to changes in the conformation of the transmembrane (TM) domain, brought about by changes in interactions of the TM helices of the membrane lipid bilayer. Using an advanced computational approach that combines Coarse-Grained molecular dynamics and well-tempered MetaDynamics (CG-MetaD), we characterize the large-scale motions of the TM helices, simulating multiple association and dissociation events between the helices in membrane, thus leading to a free energy landscape of the dimerization process. The lowest energy state of the TM domain is a right-handed dimer structure in which the TM helices interact through the N-terminal small-X3-small sequence motif. In addition to this state, which is thought to correspond to the active form of the receptor, we have identified further low-energy states that allow us to integrate with a high level of detail a range of previous experimental observations. These conformations may lead to the active state via two possible activation pathways, which involve pivoting and rotational motions of the helices, respectively. Molecular dynamics also reveals correlation between the conformational changes of the TM domains and of the intracellular juxtamembrane domains, paving the way for a comprehensive understanding of EGFR signaling at the cell membrane.
Highlights
Membrane proteins play a key role in the structure and function of cells
The dynamics of TM domains are responsible for conformational changes that underlie, e.g., receptor activation and solute transport by membrane proteins
A relatively simple and well characterized example of such interactions is provided by TM helix dimers such as those found in receptor tyrosine kinases (RTKs).[1−3]
Summary
Membrane proteins play a key role in the structure and function of cells. Most membrane proteins have transmembrane (TM) domains formed by bundles of α-helices that span the lipid bilayer. We note that the structure of the ErbB1/B2 TM helix dimer (pdb id: 2KS1) obtained by NMR in DMPC/ DHPC bicelles resembles more closely our Nter+ ensemble.[51] Another NMR structure of the EGFR TM domain plus the adjacent intracellular juxtamembrane (JM) region (pdb id: 2M20) revealed interhelix contacts at the N-terminal smallX3-small motif within the TM domain.[23] This dimer structure is very similar to the Nter+ ensemble identified as the population of lowest free-energy in our CG-MetaD calculations (Figure 8B) This agreement prompted us to undertake a series of 5 μs standard CG-MD simulations using the TM+JM NMR structure (pdb id: 2M20) as a starting conformation. EGFR can be activated either through a “pivot” motion of the TM helices and/or through an alternative “rotational” mechanism, both leading to the right-handed Nter+ active dimeric state (Figure 9C)
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