title: The disordered hypervariable region and the folded catalytic domain of oncogenic K-Ras4B partner in phospholipid binding.
abstract: The C-terminal hypervariable region (HVR) of the splice variant KRAS4B is disordered. Classically, the role of the post-translationally-modified HVR is to navigate Ras in the cell and to anchor it in localized plasma membrane regions. Here, we propose additional regulatory roles, including auto-inhibition by shielding the effector binding site in the GDP-bound state and release upon GTP binding and in the presence of certain oncogenic mutations. The released HVR can interact with calmodulin. We show that oncogenic mutations (G12V/G12D) modulate the HVR-phospholipid binding specificity, resulting in preferential interactions with phosphatidic acid. The shifts in the conformational preferences and binding specificity in the disordered state exemplify the critical role of the unstructured tail of K-Ras4B in cancer.
authors.affiliation: Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Avik
authors.initials: A
authors.lastname: Banerjee
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, USA.
authors.forename: Hyunbum
authors.initials: H
authors.lastname: Jang
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, USA; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
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
mesh_terms: D000818:Animals; D020134:Catalytic Domain / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D006801:Humans; D021962:Membrane Microdomains; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs / Q000235:genetics*; D020033:Protein Isoforms; D021381:Protein Transport; D016283:Proto-Oncogene Proteins p21(ras) / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C117307:KRAS protein, human; D010743:Phospholipids; D020033:Protein Isoforms; D016283:Proto-Oncogene Proteins p21(ras)