Structural and mechanistic insights into ras association domains of phospholipase C epsilon

Tom D Bunney, Richard Harris, Natalia Lamuño Gandarillas, Michelle B Josephs, S Mark Roe, S Caroline Sorli, Hugh F Paterson, Fernando Rodrigues-Lima, Diego Esposito, Chris P Ponting, Peter Gierschik, Laurence H Pearl, Paul C Driscoll, Matilda Katan

Research output: Contribution to journalArticlepeer-review


Ras proteins signal to a number of distinct pathways by interacting with diverse effectors. Studies of ras/effector interactions have focused on three classes, Raf kinases, ral guanylnucleotide-exchange factors, and phosphatidylinositol-3-kinases. Here we describe ras interactions with another effector, the recently identified phospholipase C epsilon (PLCepsilon). We solved structures of PLCepsilon RA domains (RA1 and RA2) by NMR and the structure of the RA2/ras complex by X-ray crystallography. Although the similarity between ubiquitin-like folds of RA1 and RA2 proves that they are homologs, only RA2 can bind ras. Some of the features of the RA2/ras interface are unique to PLCepsilon, while the ability to make contacts with both switch I and II regions of ras is shared only with phosphatidylinositol-3-kinase. Studies of PLCepsilon regulation suggest that, in a cellular context, the RA2 domain, in a mode specific to PLCepsilon, has a role in membrane targeting with further regulatory impact on PLC activity.

Original languageEnglish
Pages (from-to)495-507
Number of pages13
JournalMolecular Cell
Issue number4
Publication statusPublished - 17 Feb 2006


  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Crystallography, X-Ray
  • Enzyme Activation
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Nuclear Magnetic Resonance, Biomolecular
  • Phosphoinositide Phospholipase C
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Recombinant Fusion Proteins
  • Sequence Alignment
  • Signal Transduction
  • Thermodynamics
  • Type C Phospholipases
  • ras Proteins

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