Abstract
Rab proteins are small GTPases that act as molecular switches for intracellular vesicle trafficking. Although their function is mainly regulated by regulatory proteins such as GTPase-activating proteins and guanine nucleotide exchange factors, recent studies have shown that some Rab proteins are physiologically phosphorylated in the switch II region by Rab kinases. As the switch II region of Rab proteins undergoes a conformational change depending on the bound nucleotide, it plays an essential role in their function as a ‘switch’. Initially, the phosphorylation of Rab proteins in the switch II region was shown to inhibit the association with regulatory proteins. However, recent studies suggest that it also regulates the binding of Rab proteins to effector proteins, determining which pathways to regulate. These findings suggest that the regulation of the Rab function may be more dynamically regulated by phosphorylation than just through the association with regulatory proteins. In this review, we summarize the recent findings and discuss the physiological and pathological roles of Rab phosphorylation.
Highlights
Rab proteins are phosphorylated by Leucine-rich repeat kinase 2 (LRRK2) via the highly conserved switch II region, which regulates the hydrolysis of GTP and coordinates the binding to various regulatory proteins [8]
Rab8A is phosphorylated by the PINK1-dependent kinase at Ser111, which is different from Thr72, the site phosphorylated by LRRK2
New aspects of the regulation of the Rab function by phosphorylation have become apparent, some of which suggest a role in diseases such as Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and cancer
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. GEF activity accelerates the dissociation of GDP from the Rab protein, and this induces the binding of cytoplasmically abundant GTP to the Rab protein (reviewed in [5]). Biomolecules 2021, 11, 1340 protein initiates vesicular transport by binding to its effector proteins that selectively bind to its GTP-bound form (Figure 1A). SNARE proteins on the target membrane (t-SNARE) that promotes the fusion of the membranes (reviewed in [6]) Another is the existence of a GTPase-activating protein (GAP). The phosphorylation of Rab proteins has been shown to inhibit their interaction with GEFs and GDIs, and to let them acquire different effector proteins, suggesting the existence of alternative trafficking routes activated by Rab phosphorylation (Figure 1B,C). We summarize the recent discoveries on Rab phosphorylation and its relevance to biology and disease
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