title: High-Affinity Interaction of the K-Ras4B Hypervariable Region with the Ras Active Site.
abstract: Ras proteins are small GTPases that act as signal transducers between cell surface receptors and several intracellular signaling cascades. They contain highly homologous catalytic domains and flexible C-terminal hypervariable regions (HVRs) that differ across Ras isoforms. KRAS is among the most frequently mutated oncogenes in human tumors. Surprisingly, we found that the C-terminal HVR of K-Ras4B, thought to minimally impact the catalytic domain, directly interacts with the active site of the protein. The interaction is almost 100-fold tighter with the GDP-bound than the GTP-bound protein. HVR binding interferes with Ras-Raf interaction, modulates binding to phospholipids, and slightly slows down nucleotide exchange. The data indicate that contrary to previously suggested models of K-Ras4B signaling, HVR plays essential roles in regulation of signaling. High affinity binding of short peptide analogs of HVR to K-Ras active site suggests that targeting this surface with inhibitory synthetic molecules for the therapy of KRAS-dependent tumors is feasible.
authors.affiliation: Medicinal Chemistry Department, University of Illinois at Chicago, Chicago, Illinois; Biochemistry and Molecular Genetics Department, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Tanmay S
authors.initials: TS
authors.lastname: Chavan
authors.affiliation: Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland; Cancer and Inflammation Program, National Cancer Institute at Frederick, Frederick, Maryland.
authors.forename: Hyunbum
authors.initials: H
authors.lastname: Jang
authors.affiliation: Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland; Cancer and Inflammation Program, National Cancer Institute at Frederick, Frederick, Maryland.
authors.forename: Lyuba
authors.initials: L
authors.lastname: Khavrutskii
authors.affiliation: Biochemistry and Molecular Genetics Department, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Sherwin J
authors.initials: SJ
authors.lastname: Abraham
authors.affiliation: Chemistry Department, University of Illinois at Chicago, Chicago, Illinois; Structural Biophysics Laboratory, National Cancer Institute at Frederick, Frederick, Maryland.
authors.forename: Avik
authors.initials: A
authors.lastname: Banerjee
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute at Frederick, Frederick, Maryland.
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Freed
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute at Frederick, Frederick, Maryland.
authors.forename: Liv
authors.initials: L
authors.lastname: Johannessen
authors.affiliation: Chemistry Department, University of Illinois at Chicago, Chicago, Illinois; Structural Biophysics Laboratory, National Cancer Institute at Frederick, Frederick, Maryland.
authors.forename: Sergey G
authors.initials: SG
authors.lastname: Tarasov
authors.affiliation: Biochemistry and Molecular Genetics Department, University of Illinois at Chicago, Chicago, Illinois. Electronic address: vadimg@uic.edu.
authors.forename: Vadim
authors.initials: V
authors.lastname: Gaponenko
authors.affiliation: Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland; Cancer and Inflammation Program, National Cancer Institute at Frederick, Frederick, Maryland; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: nussinor@helix.nih.gov.
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute at Frederick, Frederick, Maryland. Electronic address: nadya.tarasova@nih.gov.
authors.forename: Nadya I
authors.initials: NI
authors.lastname: Tarasova
mesh_terms: D000595:Amino Acid Sequence; D055162:Biocatalysis; D020134:Catalytic Domain; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D016283:Proto-Oncogene Proteins p21(ras) / Q000737:chemistry* / Q000378:metabolism*; D018631:ras Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D010446:Peptide Fragments; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins