2. Academic Validation
  3. Mechanism of lipid transfer by bridge-like protein VPS13A and the scramblase XK

Mechanism of lipid transfer by bridge-like protein VPS13A and the scramblase XK

  • Cell. 2026 Jun 12:S0092-8674(26)00586-6. doi: 10.1016/j.cell.2026.05.027.
Bodan Hu 1,  Daniel Álvarez 2,  Cristian Rocha-Roa 3,  Valentin Guyard 3,  Dazhi Li 1,  Yara Ahmed 3,  Xinbo Wang 4,  Pietro De Camilli 4,  Stefano Vanni 5,  Karin M Reinisch 6
Affiliations

Affiliations

  • 1 Department of Cell Biology, Yale University School of Medicine, New Haven, CT, USA.
  • 2 Department of Biology, University of Fribourg, 1700 Fribourg, Switzerland; Department of Engineering, Universidad Loyola Andalucía, Avenida de las Universidades, Seville, Spain.
  • 3 Department of Biology, University of Fribourg, 1700 Fribourg, Switzerland.
  • 4 Department of Cell Biology, Yale University School of Medicine, New Haven, CT, USA; Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA; Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, CT, USA.
  • 5 Department of Biology, University of Fribourg, 1700 Fribourg, Switzerland; Swiss National Center for Competence in Research Bio-Inspired Materials, University of Fribourg, 1700 Fribourg, Switzerland. Electronic address: [email protected].
  • 6 Department of Cell Biology, Yale University School of Medicine, New Haven, CT, USA. Electronic address: [email protected].
PMID: 42285089 DOI: 10.1016/j.cell.2026.05.027
Abstract

In eukaryotes, bridge-like lipid-transfer proteins (BLTPs) are central in mediating vesicle-independent lipid transfer between organelles. BLTPs span the cytosolic space between organelles at contact sites, featuring hydrophobic channels for lipids to travel between membranes. How BLTPs cooperate with partner proteins to orchestrate lipid delivery remains a mystery. Here, we used cryo-electron microscopy to visualize a complex comprising the prototypical BLTP VPS13A and the plasma membrane-localized scramblase XK at near-atomic resolution. VPS13A interacts with XK via its pleckstrin homology domain, priming VPS13A's bridge-like lipid-transfer domain to deliver lipids directly to the cytosolic leaflet of the acceptor membrane. In molecular dynamics simulations, this arrangement allows for robust lipid transfer. Newly delivered lipids can then be equilibrated between leaflets of the membrane bilayer by the scramblase, allowing for membrane growth. Mechanistic insights regarding lipid delivery by VPS13A are directly applicable to all VPS13 proteins and, more broadly, to all BLTP family members.

Keywords

VPS13; XK; bridge-like lipid-transfer protein; cryo-EM; lipid transfer; membrane contact sites; molecular dynamics simulations; scramblase.

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