ARL3 activation requires the co-GEF BART and effector-mediated turnover

ElMaghloob, Y., Sot, B., McIlwraith, M. J., Garcia, E., Yelland, T. and Ismail, S. (2021) ARL3 activation requires the co-GEF BART and effector-mediated turnover. eLife, 10, e64624. (doi: 10.7554/elife.64624) (PMID:33438581) (PMCID:PMC7817177)

Abstract

The ADP-ribosylation factor-like 3 (ARL3) is a ciliopathy G-protein which regulates the ciliary trafficking of several lipid-modified proteins. ARL3 is activated by its guanine exchange factor (GEF) ARL13B via an unresolved mechanism. BART is described as an ARL3 effector which has also been implicated in ciliopathies, although the role of its ARL3 interaction is unknown. Here, we show that, at physiological GTP:GDP levels, human ARL3GDP is weakly activated by ARL13B. However, BART interacts with nucleotide-free ARL3 and, in concert with ARL13B, efficiently activates ARL3. In addition, BART binds ARL3GTP and inhibits GTP dissociation, thereby stabilising the active G-protein; the binding of ARL3 effectors then releases BART. Finally, using live cell imaging, we show that BART accesses the primary cilium and colocalises with ARL13B. We propose a model wherein BART functions as a bona fide co-GEF for ARL3 and maintains the active ARL3GTP, until it is recycled by ARL3 effectors.

• Item Type: Articles
• Additional Information: This work was supported by Cancer Research UK (CRUK core funding award A19257).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Elmaghloob, Yasmin Adel Elsayed and Garcia Gonzalez, Dr Esther and Ismail, Dr Shehab

Creator Roles

ElMaghloob, Y.: Conceptualization, Data curation, Formal analysis, Investigation, Writing – original draft, Writing – review and editing
Garcia, E.: Conceptualization, Writing – review and editing
Ismail, S.: Conceptualization, Supervision, Funding acquisition, Validation, Investigation, Writing – original draft

• Authors: ElMaghloob, Y., Sot, B., McIlwraith, M. J., Garcia, E., Yelland, T., and Ismail, S.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: eLife
• Publisher: eLife Sciences Publications
• ISSN: 2050-084X
• ISSN (Online): 2050-084X
• Copyright Holders: Copyright © 2021 ElMaghloob et al.
• First Published: First published in eLife 10: e64624
• Publisher Policy: Reproduced under a Creative Commons License