title: Computational Modeling Reveals that Signaling Lipids Modulate the Orientation of K-Ras4A at the Membrane Reflecting Protein Topology.
abstract: The structural, dynamical, and functional characterization of the small GTPase K-Ras has become a research area of intense focus due to its high occurrence in human cancers. Ras proteins are only fully functional when they interact with the plasma membrane. Here we present all-atom molecular dynamics simulations (totaling 5.8 μs) to investigate the K-Ras4A protein at membranes that contain anionic lipids (phosphatidyl serine or phosphatidylinositol bisphosphate). We find that similarly to the homologous and highly studied K-Ras4B, K-Ras4A prefers a few distinct orientations at the membrane. Remarkably, the protein surface charge and certain lipids can strongly modulate the orientation preference. In a novel analysis, we reveal that the electrostatic interaction (attraction but also repulsion) between the protein's charged residues and anionic lipids determines the K-Ras4A orientation, but that this is also influenced by the topology of the protein, reflecting the geometry of its surfaces.
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
authors.forename: Zhen-Lu
authors.initials: ZL
authors.lastname: Li
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA; Department of Neurosciences, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA; Department of Pharmacology, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA; Center for Proteomics and Bioinformatics, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA. Electronic address: matthias.buck@case.edu.
authors.forename: Matthias
authors.initials: M
authors.lastname: Buck
mesh_terms: D020134:Catalytic Domain; D006801:Humans; D008051:Lipid Bilayers / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D017434:Protein Structure, Tertiary; D016283:Proto-Oncogene Proteins p21(ras) / Q000737:chemistry*; D055672:Static Electricity
chemical_list: C117307:KRAS protein, human; D008051:Lipid Bilayers; D008565:Membrane Proteins; D016283:Proto-Oncogene Proteins p21(ras)
keywords: K-Ras4A; PIP2; Ras GTPase; anionic lipid; molecular dynamics simulation; protein complex orientation; protein topology; protein-membrane interaction; signaling lipids