title: Membrane-associated Ras dimers are isoform-specific: K-Ras dimers differ from H-Ras dimers.
abstract: Are the dimer structures of active Ras isoforms similar? This question is significant since Ras can activate its effectors as a monomer; however, as a dimer, it promotes Raf's activation and MAPK (mitogen-activated protein kinase) cell signalling. In the present study, we model possible catalytic domain dimer interfaces of membrane-anchored GTP-bound K-Ras4B and H-Ras, and compare their conformations. The active helical dimers formed by the allosteric lobe are isoform-specific: K-Ras4B-GTP favours the α3 and α4 interface; H-Ras-GTP favours α4 and α5. Both isoforms also populate a stable β-sheet dimer interface formed by the effector lobe; a less stable β-sandwich interface is sustained by salt bridges of the β-sheet side chains. Raf's high-affinity β-sheet interaction is promoted by the active helical interface. Collectively, Ras isoforms' dimer conformations are not uniform; instead, the isoform-specific dimers reflect the favoured interactions of the HVRs (hypervariable regions) with cell membrane microdomains, biasing the effector-binding site orientations, thus isoform binding selectivity.
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute at Frederick, Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, U.S.A.
authors.forename: Hyunbum
authors.initials: H
authors.lastname: Jang
authors.affiliation: Department of Chemical and Biological Engineering, Koc University, Istanbul, Turkey.
authors.forename: Serena
authors.initials: S
authors.lastname: Muratcioglu
authors.affiliation: Department of Computer Engineering, Koc University, Istanbul, Turkey.
authors.forename: Attila
authors.initials: A
authors.lastname: Gursoy
authors.affiliation: Department of Chemical and Biological Engineering, Koc University, Istanbul, Turkey.
authors.forename: Ozlem
authors.initials: O
authors.lastname: Keskin
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute at Frederick, Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, U.S.A. Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel NussinoR@helix.nih.gov.
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
mesh_terms: D000595:Amino Acid Sequence; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008074:Lipoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization / Q000235:genetics / Q000502:physiology*; D017433:Protein Structure, Secondary; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D018631:ras Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D008074:Lipoproteins; D020033:Protein Isoforms; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins; D003545:Cysteine
keywords: HVR; K-Ras4B; Raf activation; Raf dimerization; Ras interfaces; nanoclusters; plasma membrane; signalling