title: The role of G-domain orientation and nucleotide state on the Ras isoform-specific membrane interaction.
abstract: Ras proteins are proto-oncogenes that function as molecular switches linking extracellular stimuli with an overlapping but distinctive range of biological outcomes. Although modulatable interactions between the membrane and the Ras C-terminal hypervariable region (HVR) harbouring the membrane anchor motifs enable signalling specificity to be determined by their location, it is becoming clear that the spatial orientation of different Ras proteins is also crucial for their functions. To reveal the orientation of the G-domain at membranes, we conducted an extensive study on different Ras isoforms anchored to model raft membranes. The results show that the G-domain mediates the Ras-membrane interaction by inducing different sets of preferred orientations in the active and inactive states with largely parallel orientation relative to the membrane of most of the helices. The distinct locations of the different isoforms, exposing them to different effectors and regulators, coupled with different G-domain-membrane orientation, suggests synergy between this type of recognition motif and the specificity conferred by the HVR, thereby validating the concept of isoform specificity in Ras.
authors.affiliation: Physical Chemistry I, Biophysical Chemistry, Faculty of Chemistry, TU Dortmund University, Otto-Hahn-Str. 6, 44227, Dortmund, Germany.
authors.forename: Shobhna
authors.initials: S
authors.lastname: Kapoor
authors.forename: Katrin
authors.initials: K
authors.lastname: Weise
authors.forename: Mirko
authors.initials: M
authors.lastname: Erlkamp
authors.forename: Gemma
authors.initials: G
authors.lastname: Triola
authors.forename: Herbert
authors.initials: H
authors.lastname: Waldmann
authors.forename: Roland
authors.initials: R
authors.lastname: Winter
mesh_terms: D006153:Guanosine Diphosphate / Q000737:chemistry; D006160:Guanosine Triphosphate / Q000737:chemistry; D008051:Lipid Bilayers / Q000737:chemistry; D021962:Membrane Microdomains / Q000737:chemistry* / Q000378:metabolism; D018625:Microscopy, Atomic Force; D056004:Molecular Dynamics Simulation; D020033:Protein Isoforms / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D016283:Proto-Oncogene Proteins p21(ras) / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D008051:Lipid Bilayers; D020033:Protein Isoforms; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D016283:Proto-Oncogene Proteins p21(ras)