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

Eyad Kalawy Fansa, Stefanie Kristine Kösling, Eldar Zent, Alfred Wittinghofer () and Shehab Ismail ()
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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

Nature Communications, 2016, vol. 7, issue 1, 1-9

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11366

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