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PreprintCited by 6Lipid Membrane Structure and BehaviorProtein Structure and DynamicsLipid metabolism and biosynthesis

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The molecular mechanism of lipid uptake by membrane-anchored bridge-like lipid transfer proteins

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Álvarez, Daniel, Blair, Paige Chandran, Rocha-Roa, Cristian, Davey, Michael, Conibear, Elizabeth, Vanni, Stefano·2025·Proceedings of the National Academy of Sciences
DOI 10.1101/2025.08.01.668188

Preprint — published as 10.1073/pnas.2520399123 · Paper page

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Abstract

Lipid transport by bridge-like lipid transfer proteins (BLTPs) is emerging as a key process in lipid and cellular metabolism in both physiological and pathological conditions. However, the precise mechanism of lipid transport by BLTPs has remained elusive. Here, we use extensive all-atom molecular dynamics simulations to characterize the precise mechanism of lipid transfer into the BLTP hydrophobic cavity from donor membranes. For multiple BLTPs, we observe the ability to extract and solubilize lipids without lipid selectivity, and we identify membrane destabilization as a critical parameter to achieve effective lipid desorption. We rationally design a mutant BLTP with altered ability to destabilize lipid bilayers, and we show that this abolishes lipid desorption in silico and protein function in vivo . Taken together, our data provide an atomic-level description of the mechanism of lipid transport by BLTPs, ultimately suggesting alternative strategies to interfere with their activity.

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Metadata

Authors
Álvarez, D., Blair, P. C., Rocha-Roa, C., Davey, M., Conibear, E., & Vanni, S.
Affiliations
  • University of Fribourg (CH)
  • University of British Columbia (CA)
Corresponding author
Vanni, Stefano
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
openRxiv
Published
2025-08-02
Volume
123
Issue
4
Pages
e2520399123-e2520399123
ISSN
0027-8424 (ISSN-L)
DOI
10.1101/2025.08.01.668188
OpenAlex
W7125434868
Cited by
6
References
1
Citations by year
2026: 5 · 2025: 1
FWCI
10.33
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
Funders
  • Swiss National Science Foundation (CRSII5_189996)
  • European Research Council (803952)
  • Canada Foundation for Innovation (39914)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Keywords
lipid transfer, membrane perturbation, lipid solubilization, lipid metabolism, protein-lipid interactions, rational protein design
MeSH terms
Biological Transport, Carrier Proteins, Cell Membrane, Lipid Bilayers, Lipid Metabolism, Molecular Dynamics Simulation, Hydrophobic and Hydrophilic Interactions

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