Local Bilayer Reorganisation by the JM Regions of All Human RTKs: A Multiscale Molecular Dynamics Study

Abstract

The functional activity of membrane proteins is known to be modulated by lipids in the surrounding bilayer. In particular, the activity of the epidermal growth factor receptor 1 (EGFR) has recently been shown to be regulated by both GM3 in the outer leaflet[1], and by PIP2 in the inner leaflet[2]. Additionally, combined computational[3,4] and experimental[2,5] studies have demonstrated binding of the juxtamembrane (JM) region of EGFR to anionic lipids within the inner leaflet, which is thought to be functionally significant for receptor dimerization and activation.Using a multiscale molecular dynamics approach, we have explored interactions of all 58 human receptor tyrosine kinases (RTKs) with anionic membrane lipids. Our results reveal that the JM regions of these receptors are able to induce clustering of anionic lipids into ordered ring-like patterns around the transmembrane helix in both simple asymmetric bilayers, and more complex physiological bilayers which mimic the additional complexity found in vivo[6]. The behaviour we observe is driven primarily via electrostatic interactions between basic residues within the JM region, and negatively charged lipid head groups. The insights these simulations provide are of interest both for understanding RTK structure and function, and in the wider organisation of proteins and lipids within bilayers.1. U. Coskun, et al., Proc Natl Acad Sci USA, 2011, 108, 9044-82.2. I.E Michailidis, et al., Eur J Physio, 2011, 461, 387-3973.3. A. Arkhipov, et al., Cell, 2013, 152, 557-5694.4. K.B. Halim, H. Koldso, M.S.P. Sansom, Biochim Biophys Acta, 2014; http://dx.doi.org/10.1016/j.bbagen.2014.09.0065.5. C. Matsushita, et al., Proc Natl Acad Sci USA, 2012, 110, 1646-16516.6. H. Koldso, et al., PLoS Comp Biol, 2014, (in press)