A G-protein activation cascade from Arl13B to Arl3 and implications for ciliary targeting of lipidated proteins

Abstract
Article and author information
Metrics

Abstract

Small G-proteins of the ADP-ribosylation-factor-like (Arl) subfamily have been shown to be crucial to ciliogenesis and cilia maintenance. Active Arl3 is involved in targeting and releasing lipidated cargo proteins from their carriers PDE6δ and UNC119a/b to the cilium. However, the Guanine-Nucleotide-Exchange-factor (GEF) which activates Arl3 is unknown. Here we show that the ciliary G-protein Arl13B mutated in Joubert-Syndrome is the GEF for Arl3 and its function is conserved in evolution. The GEF activity of Arl13B is mediated by the G-domain plus an additional C-terminal helix. The switch regions of Arl13B are involved in the interaction with Arl3. Overexpression of Arl13B in mammalian cell lines leads to an increased Arl3•GTP level, whereas Arl13B Joubert-Syndrome patient mutations impair GEF activity and thus Arl3 activation. We anticipate that through Arl13B's exclusive ciliary localization, Arl3 activation is spatially restricted and thereby an Arl3•GTP compartment generated where ciliary cargo is specifically released.

Article and author information

Author details

Katja Gotthardt

Structural Biology Group, Max Planck Institute of Molecular Physiology, Dortmund, Germany

Competing interests
The authors declare that no competing interests exist.
Mandy Lokaj

Structural Biology Group, Max Planck Institute of Molecular Physiology, Dortmund, Germany

Competing interests
The authors declare that no competing interests exist.
Carolin Koerner

Structural Biology group, Max Planck Institute of Molecular Physiology, Dortmund, Germany

Competing interests
The authors declare that no competing interests exist.
Nathalie Falk

Department of Biology, Animal Physiology, University of Erlangen-Nuremberg, Erlangen, Germany

Competing interests
The authors declare that no competing interests exist.
Andreas Gießl

Department of Biology, Animal Physiology, University of Erlangen-Nuremberg, Erlangen, Germany

Competing interests
The authors declare that no competing interests exist.
Alfred Wittinghofer

Structural Biology Group, Max Planck Institute of Molecular Physiology, Dortmund, Germany

For correspondence
alfred.wittinghofer@mpi-dortmund.mpg.de

Competing interests
The authors declare that no competing interests exist.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.