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PreprintCited by 93Cellular transport and secretionLipid Membrane Structure and BehaviorAdvanced Electron Microscopy Techniques and Applications

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In situ architecture of the lipid transport protein VPS13C at ER-lysosomes membrane contacts

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Cai, Shujun, Wu, Yumei, Guillen-Samander, Andres, Hancock-Cerutti, William, Liu, Jun, De Camilli, Pietro·2022·Proceedings of the National Academy of Sciences
DOI 10.1101/2022.03.08.482579PMC PMC9303930

Preprint — published as 10.1073/pnas.2203769119 · Paper page

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Abstract

VPS13 is a eukaryotic lipid transport protein localized at membrane contact sites. Previous studies suggested that it may transfer lipids between adjacent bilayers by a bridge-like mechanism. Direct evidence for this hypothesis from a full-length structure and from EM studies in situ , however, is still missing. Here we have capitalized on AlphaFold predictions to complement the structural information already available about VPS13 and to generate a full-length model of human VPS13C, the Parkinson’s disease-linked VPS13 paralog localized at contacts between the ER and endo/lysosomes. Such model predicts a ~30-nm rod with a hydrophobic groove that extends throughout its length. We further investigated whether such a structure can be observed in situ at ER-endo/lysosome contacts. To this aim, we combined genetic approaches with cryo-focused-ion-beam (cryo-FIB) milling and cryo-electron tomography (cryo-ET) to examine HeLa cells overexpressing this protein (either full length or with an internal truncation) along with VAP, its anchoring binding partner at the ER. Using these methods we identified rod-like densities that span the space separating the two adjacent membranes and that match the predicted structures of either full length VPS13C or its shorter truncated mutant, thus providing the first in-situ evidence for a bridge-model of VPS13 in lipid transport. Intriguingly, the majority of the VPS13C rods were separated from the ER membranes by a narrow gap, suggesting that while VAP anchors the protein to the ER, direct contact of the VPS13C rod with the ER bilayer to allow lipid transport may be independently regulated.

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Metadata

Authors
Cai, S., Wu, Y., Guillen-Samander, A., Hancock-Cerutti, W., Liu, J., & De Camilli, P.
Affiliations
  • Howard Hughes Medical Institute (US)
  • Yale University (US)
Corresponding author
Liu, Jun
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
openRxiv
Published
2022-03-08
Volume
119
Issue
29
Pages
e2203769119-e2203769119
ISSN
0027-8424 (ISSN-L)
DOI
10.1101/2022.03.08.482579
PMC
PMC9303930
OpenAlex
W4285088070
Cited by
93
References
1
Citations by year
2026: 17 · 2025: 23 · 2024: 28 · 2023: 15 · 2022: 10
FWCI
10.16
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Howard Hughes Medical Institute
  • Yale University
  • Aligning Science Across Parkinson’s (ASAP-000580)
  • National University of Singapore
  • National Institutes of Health (NS36251, DA-018343)
  • National Institute on Drug Abuse (P30DA018343)
  • National Institute of Allergy and Infectious Diseases (R01AI152421)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK045735)
  • National Institute of Neurological Disorders and Stroke (R01NS036251, R37NS036251)
  • Yale Liver Center
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Advanced Electron Microscopy Techniques and Applications
Keywords
VPS13C, Vps13, lipid transport, membrane contact sites, endoplasmic reticulum, lysosomes, bridge model, protein structure, Parkinson's disease, ventilator-associated pneumonia, cryo-electron tomography, cryo-focused ion beam milling, HeLa cells
MeSH terms
Bacterial Outer Membrane Proteins, Biological Transport, Cell Membrane, Endoplasmic Reticulum, HeLa Cells, Humans, Lysosomes, Proteins, ATP-Binding Cassette Transporters, Cryoelectron Microscopy, Lipid Metabolism

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