title: GTP-Dependent K-Ras Dimerization.
abstract: Ras proteins recruit and activate effectors, including Raf, that transmit receptor-initiated signals. Monomeric Ras can bind Raf; however, activation of Raf requires its dimerization. It has been suspected that dimeric Ras may promote dimerization and activation of Raf. Here, we show that the GTP-bound catalytic domain of K-Ras4B, a highly oncogenic splice variant of the K-Ras isoform, forms stable homodimers. We observe two major dimer interfaces. The first, highly populated β-sheet dimer interface is at the Switch I and effector binding regions, overlapping the binding surfaces of Raf, PI3K, RalGDS, and additional effectors. This interface has to be inhibitory to such effectors. The second, helical interface also overlaps the binding sites of some effectors. This interface may promote activation of Raf. Our data reveal how Ras self-association can regulate effector binding and activity, and suggest that disruption of the helical dimer interface by drugs may abate Raf signaling in cancer.
authors.affiliation: Department of Chemical and Biological Engineering, Koc University, Rumelifeneri Yolu, 34450 Sariyer Istanbul, Turkey.
authors.forename: Serena
authors.initials: S
authors.lastname: Muratcioglu
authors.affiliation: Department of Medicinal Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA; Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Tanmay S
authors.initials: TS
authors.lastname: Chavan
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Freed
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute at Frederick, Frederick, MD 21702, USA; Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors.forename: Hyunbum
authors.initials: H
authors.lastname: Jang
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute at Frederick, Frederick, MD 21702, USA; Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors.forename: Lyuba
authors.initials: L
authors.lastname: Khavrutskii
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
authors.forename: R Natasha
authors.initials: RN
authors.lastname: Freed
authors.affiliation: Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA; Structural Biophysics Laboratory, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
authors.forename: Marzena A
authors.initials: MA
authors.lastname: Dyba
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Stefanisko
authors.affiliation: Structural Biophysics Laboratory, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
authors.forename: Sergey G
authors.initials: SG
authors.lastname: Tarasov
authors.affiliation: Department of Computer Engineering, Koc University, Rumelifeneri Yolu, 34450 Sariyer Istanbul, Turkey.
authors.forename: Attila
authors.initials: A
authors.lastname: Gursoy
authors.affiliation: Department of Chemical and Biological Engineering, Koc University, Rumelifeneri Yolu, 34450 Sariyer Istanbul, Turkey.
authors.forename: Ozlem
authors.initials: O
authors.lastname: Keskin
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
authors.forename: Nadya I
authors.initials: NI
authors.lastname: Tarasova
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA. Electronic address: vadimg@uic.edu.
authors.forename: Vadim
authors.initials: V
authors.lastname: Gaponenko
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute at Frederick, Frederick, MD 21702, USA; Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: nussinor@helix.nih.gov.
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
mesh_terms: D020134:Catalytic Domain; D006160:Guanosine Triphosphate / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D016283:Proto-Oncogene Proteins p21(ras) / Q000737:chemistry*
chemical_list: C117307:KRAS protein, human; D006160:Guanosine Triphosphate; D016283:Proto-Oncogene Proteins p21(ras)