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

Fansa, E. K., Kösling, S. K., Zent, E., Wittinghofer, A. and Ismail, S. (2016) PDE6δ-mediated sorting of INPP5E into the cilium is determined by cargo-carrier affinity. Nature Communications, 7, 11366. (doi: 10.1038/ncomms11366) (PMID:27063844) (PMCID:PMC5512577)

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 destinatio

• Item Type: Articles
• Additional Information: The funding was supported by the European Research Council (ERC Grant 268782), Sonderforschungsbereich-DFG (SFB 642) and CRUK core funding award to S.I. (A19257).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Ismail, Dr Shehab
• Authors: Fansa, E. K., Kösling, S. K., Zent, E., Wittinghofer, A., and Ismail, S.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Communications
• Publisher: Nature Publishing Group
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2016 The Authors
• First Published: First published in Nature Communications 7:11366
• Publisher Policy: Reproduced under a Creative Commons License