PreprintCited by 3Cellular transport and secretionExtracellular vesicles in diseaseMicrotubule and mitosis dynamics

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Continuum architecture dynamics of vesicle tethering in exocytosis

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Preprint — published as 10.1016/j.cell.2025.11.038 · Paper page

Abstract

SUMMARY: Essential for eukaryotic organisms, multiple copies of the exocyst complex tether each secretory vesicle to the plasma membrane (PM) in constitutive exocytosis. The exocyst higher-order structure (ExHOS) that coordinates the action of these multiple exocysts remains unexplored. We integrated particle-tracking, super-resolution microscopy and cryo-electron tomography in a model that time-resolves the continuum conformational landscape of the ExHOS and functionally annotates its different conformations. We found that 7 exocysts form flexible ring-shaped ExHOS that tether vesicles at <45 nm from the PM. The ExHOS, initially 19 nm in radius, rapidly expands while it pulls the vesicle towards the PM. Subsequently, the ExHOS stabilizes, securing the vesicle at ∼4 nm from the PM. After fusion, Sec18 mediates the ExHOS disassembly when its radius is 38 nm. By resolving the fundamental biophysical principles of tethering we bridged the gap between static isolated structures and the dynamic and multimeric nature of exocytosis.

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Metadata

Authors
Puig-Tintó, M., Ortiz, S., Meek, S., Coray, R., Hernández, A. C., Castellet, A., Kramer, E., Betancur, L. I., Hoess, P., Mund, M., Izquierdo-Serra, M., Oliva, B., de Marco, A., Ries, J., Castaño-Díez, D., Manzo, C., & Gallego, O.
Affiliations
  • Department of Medicine and Life Sciences (MELIS), Universitat Pompeu Fabra (UPF), Barcelona, Spain
  • Universitat Pompeu Fabra (ES)
  • University of the Basque Country (ES)
  • European Molecular Biology Laboratory (DE)
  • Universitat de Barcelona (ES)
  • New York Structural Biology Center (US)
  • University of Vienna (AT)
  • Instituto Biofisika (UPV/EHU, CSIC), University of the Basque Country, Leioa, Spain
  • Universitat de Vic - Universitat Central de Catalunya (ES)
Corresponding author
  • Ries, Jonas
  • Manzo, Carlo
  • Gallego, Oriol
Venue
Cell
Publisher
openRxiv
Published
2025-02-05
Volume
189
Issue
4
Pages
1170-1184.e22
ISSN
0092-8674 (ISSN-L)
OpenAlex
W7124435907
Cited by
3
References
1
Citations by year
2026: 2 · 2025: 1
FWCI
6.76
Type
journal article
Language
en
Open access
Locations
  • Cell (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
  • Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion, cc-by)
Funders
  • European Molecular Biology Laboratory
  • Human Frontier Science Program
  • Boehringer Ingelheim Stiftung
  • Agencia Estatal de Investigación (AEI//10.13039/501100011033/, 501100011033, PID2021-127309NB-I00, MICIU/AEI /10.13039/501100011033, 10.13039/501100011033, 13039, .13039/501100011033, 10.13039, 501100011033/FEDER, AEI/10, #CEX2018-000792-M)
  • National Institute of General Medical Sciences (U24GM139171)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
Keywords
exocyst complex, vesicle tethering, exocytosis, Sec18, vesicle fusion, plasma membrane, metastable states, secretory vesicles, conformational dynamics, particle tracking, cryo-electron tomography
MeSH terms
Animals, Cell Membrane, Exocytosis, Saccharomyces cerevisiae, Cryoelectron Microscopy, Secretory Vesicles, Saccharomyces cerevisiae Proteins, Vesicular Transport Proteins, Electron Microscope Tomography

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