The Vps13p–Cdc31p complex is directly required for TGN late endosome transport and TGN homotypic fusion

De, Mithu; Oleskie, Austin N.; Ayyash, Mariam; Dutta, Somnath; Mancour, Liliya; Abazeed, Mohamed E.; Brace, E. J.; Skiniotis, Georgios; Fuller, Robert S.

doi:10.1083/jcb.201606078

Cited by 78 publications

(128 citation statements)

References 59 publications

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“…This is unexpected because both N‐terminal and C‐terminal regions are evolutionarily conserved and similar to the corresponding regions in VPS13A. An in vitro liposome experiment showed that yeast Vps13 can directly bind to membranes, especially those containing phosphatidic acid and phosphatidylinositol phosphates . In particular, the N‐terminal region of Vps13 showed a high affinity to phosphatidic acid and a weak affinity to PtdIns4,5P 2 and PtdIns4P, whereas the C‐terminal region showed an affinity to PtdIns4,5P 2 .…”

Section: Discussionmentioning

confidence: 99%

Differential requirement for ATG2A domains for localization to autophagic membranes and lipid droplets

et al. 2017

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ATG2 is one of the autophagy-related (ATG) proteins essential for autophagosome formation and localizes to isolation membranes and lipid droplets in mammalian cells. Here, we investigated the requirement of regions in ATG2A for its organellar localization and function. The N-terminal amino acids 1-198 and the C-terminal amino acids 1830-1938 are required for the localization to isolation membranes and lipid droplets, respectively. The C-terminal region is not required for the localization to isolation membranes and for autophagy. We also identified an amphipathic helix in ATG2A that is required for both its localization to organelles and autophagosome formation. These data suggest that the dual localization of ATG2A is regulated by different regions.

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Section: Discussionmentioning

confidence: 99%

Differential requirement for ATG2A domains for localization to autophagic membranes and lipid droplets

et al. 2017

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“…Recent work suggests that Vps13 is required for normal sorting of Neo1 flippase on endosomes . The observed defects in Golgi‐to‐vacuole transport and in endocytosis might occur as the result of misregulation of common components of both pathways or as a direct consequence of Vps13 deficiency, as it has been reported recently that Vps13 is directly required for Golgi‐to‐endosome transport and trans‐Golgi homotypic fusion in vitro …”

Section: Yeast As a Model To Study Vps13 Proteinsmentioning

confidence: 94%

“…Vps13 is folded into a compact rod shape (20 × 4 nm) with a flexible portion in the middle, a characteristic loop structure with internal diameter of ∼6 nm at one end and a hook‐like region on the opposite end. Such ending structures can be facing the same or opposite directions suggesting the possibility of rotation (Figure B) . The position of the N‐ and C‐terminal regions in this structure is still unknown.…”

Section: Yeast As a Model To Study Vps13 Proteinsmentioning

confidence: 98%

“…The position of the N‐ and C‐terminal regions in this structure is still unknown. Vps13 was very recently found to be a lipid‐binding protein as it binds to phosphatidic acid (PA), mono‐ and bisphosphorylated phosphatidylinositol derivatives (PIP and PIP 2 , respectively), lysophosphatidic acid (LPA) and, with very low affinity, to phosphatidylserine (PS) . Interestingly, Vps13 possesses at least 4 lipid‐binding regions, which may independently bind to different phospholipids: the N terminus (aa 1‐437) interacts with PA, PI(4,5)P 2 , and PI4P; the C terminus (aa 2905‐3144) binds to PI(4,5)P 2 ; the central SHR_BD domain containing region (aa 2158‐2575) binds all phosphorylated phosphatidylinositol derivatives (PIPs), PA and LPA; and the APT1 domain region (aa 2492‐2844) interacts almost exclusively with PI3P (Figure A) …”

Section: Yeast As a Model To Study Vps13 Proteinsmentioning

confidence: 99%

Section: Yeast As a Model To Study Vps13 Proteinsmentioning

confidence: 99%

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Yeast and other lower eukaryotic organisms for studies of Vps13 proteins in health and disease

Rzepnikowska

Flis

Muñoz-Braceras

et al. 2017

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Human Vps13 proteins are associated with several diseases, including the neurodegenerative disorder Chorea-acanthocytosis (ChAc), yet the biology of these proteins is still poorly understood. Studies in Saccharomyces cerevisiae, Dictyostelium discoideum, Tetrahymena thermophila and Drosophila melanogaster point to the involvement of Vps13 in cytoskeleton organization, vesicular trafficking, autophagy, phagocytosis, endocytosis, proteostasis, sporulation and mitochondrial functioning. Recent findings show that yeast Vps13 binds to phosphatidylinositol lipids via 4 different regions and functions at membrane contact sites, enlarging the list of Vps13 functions. This review describes the great potential of simple eukaryotes to decipher disease mechanisms in higher organisms and highlights novel insights into the pathological role of Vps13 towards ChAc.

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Identification of two compound heterozygous VPS13A large deletions in chorea‐acanthocytosis only by protein and quantitative DNA analysis

Spieler

Velayos‐Baeza

Mühlbäck

et al. 2020

Molec Gen & Gen Med

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Background Chorea‐acanthocytosis (ChAc; OMIM #200150) is a rare autosomal recessive condition with onset in early adulthood that is caused by mutations in the vacuolar protein sorting 13A (VPS13A) gene encoding chorein. Several diagnostic genomic DNA (gDNA) sequencing approaches are widely used. However, their limitations appear not to be acknowledged thoroughly enough. Methods Clinically, we deployed magnetic resonance imaging, blood smear analysis, and clinical chemistry for the index patient's characterization. The molecular analysis of the index patient next to his parents covered genomic DNA (gDNA) sequencing approaches, RNA/cDNA sequencing, and chorein specific Western blot. Results We report a 33‐year‐old male patient without functional protein due to compound heterozygosity for two VPS13A large deletions of 1168 and 1823 base pairs (bp) affecting, respectively, exons 8 and 9, and exon 13. To our knowledge, this represents the first ChAc case with two compound heterozygous large deletions identified so far. Of note, standard genomic DNA (gDNA) Sanger sequencing approaches alone yielded false negative findings. Conclusion Our case demonstrates the need to carry out detection of chorein in patients suspected of having ChAc as a helpful and potentially decisive tool to establish diagnosis. Furthermore, the course of the molecular analysis in this case discloses diagnostic pitfalls in detecting some variations, such as deletions, using only standard genomic DNA (gDNA) Sanger sequencing approaches and exemplifies alternative methods, such as RNA/cDNA sequencing or qRT‐PCR analysis, necessary to avoid false negative results.

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The Vps13p–Cdc31p complex is directly required for TGN late endosome transport and TGN homotypic fusion

Cited by 78 publications

References 59 publications

Differential requirement for ATG2A domains for localization to autophagic membranes and lipid droplets

Differential requirement for ATG2A domains for localization to autophagic membranes and lipid droplets

Yeast and other lower eukaryotic organisms for studies of Vps13 proteins in health and disease

Identification of two compound heterozygous VPS13A large deletions in chorea‐acanthocytosis only by protein and quantitative DNA analysis

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