PDE6?-mediated sorting of INPP5E into the cilium is determined by cargo-carrier affinity.

ABSTRACT: The phosphodiesterase 6 delta subunit (PDE6?) 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 PDE6? 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 PDE6?/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 PDE6? and the release by Arl2/3 in addition to a retention signal are the determinants for cargo sorting and enrichment at its destination.

SUBMITTER: Fansa EK 

PROVIDER: S-EPMC5512577 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature