Energetics of ErbB1 Transmembrane Domain Dimerization in Lipid Bilayers

Abstract

One of the most extensively studied receptor tyrosine kinases is EGFR/ErbB1. Although our knowledge of the role of the extracellular domains and ligands in ErbB1 activation has increased dramatically based on solved domain structures, the exact mechanism of signal transduction across the membrane remains unknown. The transmembrane domains are expected to play an important role in the dimerization process, but the contribution of ErbB1 TM domain to dimer stability is not known, with published results contradicting one another. We address this controversy by showing that ErbB1 TM domain dimerizes in lipid bilayers and by calculating its contribution to stability as -2.5 kcal/mol. The stability calculations use two different methods based on Förster resonance energy transfer, which give the same result. The ErbB1 TM domain contribution to stability exceeds the change in receptor tyrosine kinases dimerization propensities that can convert normal signaling processes into pathogenic processes, and is thus likely important for biological function.

Characterization of Membrane Protein Interactions by Isothermal Titration Calorimetry

“…7b) and favorable contributions from helix-helix preorientation present in lipid bilayer are absent. However, this bicelle condition provides ideal solvent conditions [17] Table 1. more stable than fibroblast growth factor receptor 3 and epidermal growth factor receptor complexes such as Erb4 (more than − 3 kcal/mol) but surpassed by the relatively strong glycophorin A homodimer (less than − 7 kcal/mol) [9,12,17,40,41]. Integrin αIIbβ3 TM complex stability therefore resides between pure signaling receptors and the more structural protein glycophorin A.…”

Receptor tyrosine kinase transmembrane domains

“…So far, three different TM domains from three different RTK subfamilies have been characterized in terms of their homodimerization energetics in lipid bilayers, the TM domains of ErbB1, FGFR3 and EphA1. [28][29][30] The strengths of interactions for these three RTK TM domains are very similar, about -3 kcal/mole.…”

Analysis of the Role of the C-Terminal Tail in the Regulation of the Epidermal Growth Factor Receptor

“…A key step in switching on the receptor is the formation of an asymmetric dimer of the kinase domains, in which one kinase, termed the activator, allosterically activates the other one, termed the receiver (12)(13)(14)(15)(16)(17). The transmembrane helices of the receptors also dimerize (18)(19)(20).…”