The GTPase Arf1 Is a Determinant of Yeast Vps13 Localization to the Golgi Apparatus

Kolakowski, Damian; Rzepnikowska, Weronika; Kaniak-Golik, Aneta; Żołądek, Teresa; Kamińska, Joanna

doi:10.3390/ijms222212274

Cited by 19 publications

(30 citation statements)

References 89 publications

(135 reference statements)

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“…S. cerevisiae Vps13 localizes to multiple MCSs, including the Nuclear Vacuolar Junction (NVJ), the vacuole-mitochondria patch (vCLAMP) and endosome-mitochondrial contact sites ( Dziurdzik and Conibear, 2021 ). In addition, S. cerevisiae Vps13 localizes to prospore membranes ( Park and Neiman, 2012 ), the Golgi apparatus ( Kolakowski et al, 2021 ) and peroxisomes ( John Peter et al, 2017 ). Most likely H. polymorpha Vps13 also localizes to multiple organelles.…”

Section: Discussionmentioning

confidence: 99%

Yeast Vps13 is Crucial for Peroxisome Expansion in Cells With Reduced Peroxisome-ER Contact Sites

Yuan

Akşit

Boer

et al. 2022

Front. Cell Dev. Biol.

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In the yeast Hansenula polymorpha the peroxisomal membrane protein Pex11 and three endoplasmic reticulum localized proteins of the Pex23 family (Pex23, Pex24 and Pex32) are involved in the formation of peroxisome-ER contact sites. Previous studies suggested that these contacts are involved in non-vesicular lipid transfer and important for expansion of the peroxisomal membrane. The absence of Pex32 results in a severe peroxisomal phenotype, while cells lacking Pex11, Pex23 or Pex24 show milder defects and still are capable to form peroxisomes and grow on methanol. We performed transposon mutagenesis on H. polymorpha pex11 cells and selected mutants that lost the capacity to grow on methanol and are severely blocked in peroxisome formation. This strategy resulted in the identification of Vps13, a highly conserved contact site protein involved in bulk lipid transfer. Our data show that peroxisome formation and function is normal in cells of a vps13 single deletion strain. However, Vps13 is essential for peroxisome biogenesis in pex11. Notably, Vps13 is also required for peroxisome formation in pex23 and pex24 cells. These data suggest that Vps13 is crucial for peroxisome formation in cells with reduced peroxisome-endoplasmic reticulum contact sites and plays a redundant function in lipid transfer from the ER to peroxisomes.

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Section: Discussionmentioning

confidence: 99%

Yeast Vps13 is Crucial for Peroxisome Expansion in Cells With Reduced Peroxisome-ER Contact Sites

Yuan

Akşit

Boer

et al. 2022

Front. Cell Dev. Biol.

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“…This region is followed by a PH-like domain which generally interacts with phosphoinositides (Fidler et al, 2016). Extensively studied in yeast and human VPS13A, this PH-like domain was shown to bind Arf1 GTPase and bis and tris -phosphorylated phosphoinositides (Kolakowski et al, 2021). As our in silico approach and protein-membrane simulations did not predict the PH-like domains to exhibit significant hydrophobicity nor to be positively charged and to disturb lipid surfaces, suggesting membrane targeting interactions only (Videos S1-S4).…”

Section: Discussionmentioning

confidence: 99%

“…We undertake an in silico approach to investigate possible mechanisms of the VPS13 lipid transfer function. An N-terminal hydrophobic groove was previously found to solubilise tens of lipid fatty acid moieties (Adlakha et al, 2022; Kolakowski et al, 2021; Kumar et al, 2018) and extends across the bulk length of the protein in the form of β-strand repeats and their laterally connected α-helices or unstructured peptides, giving rise to the recently named repeating β-groove (RBG) domain (Neuman et al, 2022). Recognition motifs and protein-binding domains decorate VPS13s along their lipid transferring channels, which span across intermembrane contact sites that may vary between ∼10-40 nm in distance (Cai et al, 2022; Neuman et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, VPS13A is thought to act as an intermembrane bridge for the transfer of lipid cargo at ER-mitochondria, ER-lipid droplet, and mitochondria-endosome contact sites (Kumar et al, 2018; Li et al, 2020; Muñoz-Braceras et al, 2019; Ugur et al, 2020). Within its interactome, previous work found that VPS13A binds the lipid scramblase XK (Park and Neiman, 2020), Arf1 GTPase and bis- and tris -phosphorylated phosphoinositide lipids (Kolakowski et al, 2021). The closest paralog to VPS13A is VPS13C (Kumar et al, 2018), whose dysregulation, importantly, contributes to the progression and development of Parkinson’s disease (Lesage et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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In silico modelling human VPS13 proteins associated with donor and target membranes suggests lipid transfer mechanisms

Armellina

Stagi

Swan

2022

Preprint

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The VPS13 protein family constitutes a novel class of bridge-like lipid transferases. Autosomal recessive inheritance of mutations in VPS13 genes is associated with the development of neurodegenerative diseases in humans. Bioinformatic approaches previously recognised the domain architecture of these proteins. In this study, we model the first ever full-length structures of the four human homologs VPS13A, VPS13B, VPS13C, and VPS13D in association with model membranes, to investigate their lipid transfer ability and potential structural association with membrane leaflets. We analyse the evolutionary conservation and physicochemical properties of these proteins, focusing on conserved C-terminal amphipathic helices that disturb organelle surfaces and that, adjoined, resemble a traditional Venetian gondola. The gondola domains share significant structural homology with lipid droplet surface-binding proteins. We introduce in silico protein-membrane models displaying the mode of association of VPS13A, VPS13B, VPS13C, and VPS13D to donor and target membranes, and present potential models of action for protein-mediated lipid transfer.

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“…However it is becoming clear that Vps13 recruitment and function is more complex than this simple paradigm. For example, a recent report in yeast showed that the Arf1 protein binds to the PH domain of Vps13 to recruit Vps13 to the Golgi (Kolakowski et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Interaction between VPS13A and the XK scramblase is required to prevent VPS13A disease in humans

Park

Hollingsworth

et al. 2022

Preprint

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VPS13 family proteins form conduits between the membranes of different organelles through which lipids are transferred. In humans there are four VPS13 paralogs each of which is required to prevent a different inherited disorder. VPS13 proteins contain multiple conserved domains. The VAB domain binds to adaptor proteins to recruit VPS13 to specific membrane contact sites. This work demonstrates the importance of a different domain in VPS13A in preventing VPS13A disease (chorea-acanthocytosis). The Pleckstrin Homology (PH) domain at the C-terminus of VPS13A is required to form a complex with the XK scramblase and for proper localization of VPS13A within the cell. Mutations in the interaction surface between VPS13A and XK predicted by Alphafold modeling disrupt complex formation and colocalization of the two proteins. Mutant VPS13A alleles found in patients with VPS13A disease truncate the PH domain. The phenotypic similarities between VPS13A disease and McLeod syndrome caused by mutations in XK argue that loss of VPS13A-XK complex is the basis of both diseases.Summary StatementVPS13A disease and McLeod syndrome are related disorders caused by mutation of the VPS13A and XK genes, respectively. A pathologic VPS13A mutation disrupts binding of the VPS13A and XK proteins, suggesting a common basis of both diseases.

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The GTPase Arf1 Is a Determinant of Yeast Vps13 Localization to the Golgi Apparatus

Cited by 19 publications

References 89 publications

Yeast Vps13 is Crucial for Peroxisome Expansion in Cells With Reduced Peroxisome-ER Contact Sites

Yeast Vps13 is Crucial for Peroxisome Expansion in Cells With Reduced Peroxisome-ER Contact Sites

In silico modelling human VPS13 proteins associated with donor and target membranes suggests lipid transfer mechanisms

Interaction between VPS13A and the XK scramblase is required to prevent VPS13A disease in humans

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