Abstract
VPS13 proteins are evolutionarily conserved. Mutations in the four human genes (VPS13A-D) encoding VPS13A-D proteins are linked to developmental or neurodegenerative diseases. The relationship between the specific localization of individual VPS13 proteins, their molecular functions, and the pathology of these diseases is unknown. Here we used a yeast model to establish the determinants of Vps13′s interaction with the membranes of Golgi apparatus. We analyzed the different phenotypes of the arf1-3 arf2Δ vps13∆ strain, with reduced activity of the Arf1 GTPase, the master regulator of Golgi function and entirely devoid of Vps13. Our analysis led us to propose that Vps13 and Arf1 proteins cooperate at the Golgi apparatus. We showed that Vps13 binds to the Arf1 GTPase through its C-terminal Pleckstrin homology (PH)-like domain. This domain also interacts with phosphoinositol 4,5-bisphosphate as it was bound to liposomes enriched with this lipid. The homologous domain of VPS13A exhibited the same behavior. Furthermore, a fusion of the PH-like domain of Vps13 to green fluorescent protein was localized to Golgi structures in an Arf1-dependent manner. These results suggest that the PH-like domains and Arf1 are determinants of the localization of VPS13 proteins to the Golgi apparatus in yeast and humans.
Highlights
VPS13 proteins belong to an evolutionarily conserved family of proteins
To further explore the role of Vps13 in trafficking, especially in the late secretory pathway and in endocytosis, we investigated the co-localization of Vps13 tagged with green fluorescence protein, Vps13-GFP, with clathrin
We used the observation that Mcp1 overproduced f a plasmid causes Vps13 to be almost exclusively attached to mitochondria [7], In summary, these results show that both Vps13 and Arf1 are important for mitochondrial functions, but that they participate in two separate, complementary pathways
Summary
Vps protein was the founding member of this family. Four human members of the family have been identified (VPS13A-D). The first data relating to their molecular function came from a yeast study in which Vps was found to be present in several membrane contact sites (MCSs) [5,6,7]. MCSs are structures in which the membranes of two organelles are maintained in close proximity, but do not fuse [8]. These sites are responsible for lipid and ion transport between organelles, and are important for lipid biosynthesis and communication between organelles. VPS13A was shown to be present at ER-mitochondria and at ER-lipid droplet MCSs [9], VPS13B at MCSs between recycling endosomes and early endosomes [10], and VPS13C at MCSs between the ER and endosomes [9] and VPS13D at ER-mitochondria, ER-peroxisome [11,12], and lipid droplet–mitochondria MCSs [13]
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