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PDE6δ-mediated sorting of INPP5E into the cilium is determined by cargo-carrier affinity

Author

Listed:
  • Eyad Kalawy Fansa

    (Max Planck Institute of Molecular Physiology)

  • Stefanie Kristine Kösling

    (Max Planck Institute of Molecular Physiology)

  • Eldar Zent

    (Max Planck Institute of Molecular Physiology)

  • Alfred Wittinghofer

    (Max Planck Institute of Molecular Physiology)

  • Shehab Ismail

    (CR-UK Beatson Institute)

Abstract

The phosphodiesterase 6 delta subunit (PDE6δ) shuttles several farnesylated cargos between membranes. The cargo sorting mechanism between cilia and other compartments is not understood. Here we show using the inositol polyphosphate 5′-phosphatase E (INPP5E) and the GTP-binding protein (Rheb) that cargo sorting depends on the affinity towards PDE6δ and the specificity of cargo release. High-affinity cargo is exclusively released by the ciliary transport regulator Arl3, while low-affinity cargo is released by Arl3 and its non-ciliary homologue Arl2. Structures of PDE6δ/cargo complexes reveal the molecular basis of the sorting signal which depends on the residues at the −1 and −3 positions relative to farnesylated cysteine. Structure-guided mutation allows the generation of a low-affinity INPP5E mutant which loses exclusive ciliary localization. We postulate that the affinity to PDE6δ and the release by Arl2/3 in addition to a retention signal are the determinants for cargo sorting and enrichment at its destination.

Suggested Citation

  • Eyad Kalawy Fansa & Stefanie Kristine Kösling & Eldar Zent & Alfred Wittinghofer & Shehab Ismail, 2016. "PDE6δ-mediated sorting of INPP5E into the cilium is determined by cargo-carrier affinity," Nature Communications, Nature, vol. 7(1), pages 1-9, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11366
    DOI: 10.1038/ncomms11366
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