Arl2-GTP and Arl3-GTP regulate a GDI-like transport system for farnesylated cargo

Nat Chem Biol. 2011 Oct 16;7(12):942-9. doi: 10.1038/nchembio.686.


Lipidated Rho and Rab GTP-binding proteins are transported between membranes in complex with solubilizing factors called 'guanine nucleotide dissociation inhibitors' (GDIs). Unloading from GDIs using GDI displacement factors (GDFs) has been proposed but remains mechanistically elusive. PDEδ is a putative solubilizing factor for several prenylated Ras-subfamily proteins. Here we report the structure of fully modified farnesylated Rheb-GDP in complex with PDEδ. The structure explains the nucleotide-independent binding of Rheb to PDEδ and the relaxed specificity of PDEδ. We demonstrate that the G proteins Arl2 and Arl3 act in a GTP-dependent manner as allosteric release factors for farnesylated cargo. We thus describe a new transport system for farnesylated G proteins involving a GDI-like molecule and an unequivocal GDF. Considering the importance of PDEδ for proper Ras and Rheb signaling, this study is instrumental in developing a new target for anticancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-Ribosylation Factors / chemistry
  • ADP-Ribosylation Factors / metabolism*
  • Animals
  • Biological Transport
  • Cells, Cultured
  • Cyclic Nucleotide Phosphodiesterases, Type 6 / chemistry
  • Cyclic Nucleotide Phosphodiesterases, Type 6 / metabolism*
  • Dogs
  • GTP-Binding Proteins / chemistry
  • GTP-Binding Proteins / metabolism*
  • Guanosine Triphosphate / chemistry
  • Guanosine Triphosphate / metabolism*
  • Humans
  • Models, Molecular
  • Prenylation
  • Protein Conformation


  • Guanosine Triphosphate
  • Cyclic Nucleotide Phosphodiesterases, Type 6
  • ARL2 protein, human
  • Arl2 protein, mouse
  • GTP-Binding Proteins
  • Arl3 protein, mouse
  • ADP-Ribosylation Factors
  • ARL3 protein, human

Associated data

  • PDB/3T5G
  • PDB/3T5I