The disordered hypervariable region and the folded catalytic domain of oncogenic K-Ras4B partner in phospholipid binding

Curr Opin Struct Biol. 2016 Feb;36:10-7. doi: 10.1016/j.sbi.2015.11.010. Epub 2015 Dec 20.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Catalytic Domain / genetics*
  • Gene Expression Regulation, Neoplastic
  • Genetic Variation*
  • Humans
  • Membrane Microdomains
  • Mutation
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Phospholipids / chemistry
  • Phospholipids / metabolism*
  • Protein Binding
  • Protein Folding
  • Protein Interaction Domains and Motifs / genetics*
  • Protein Isoforms
  • Protein Transport
  • Proto-Oncogene Proteins p21(ras) / chemistry
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Signal Transduction

Substances

  • Phospholipids
  • Protein Isoforms
  • K-Ras4B protein, human
  • Proto-Oncogene Proteins p21(ras)