Structural flexibility of the human vault particle revealed by high-resolution cryo-EM and molecular dynamics simulations

Vaults are massive ribonucleoprotein complexes, highly conserved and abundant in eukaryotic cells, yet with unclear function. Their thin-walled barrel-shape architecture is composed of two symmetrical, antiparallel half-shells, each containing 39 copies of the major vault protein (MVP). The spacious lumen of the vault suggests a role in cellular transport. Although vaults are thought to undergo conformational changes to facilitate cargo exchange, the molecular basis for their inherent flexibility remains unknown. Here, we integrate cryogenic electron microscopy (cryo-EM) and multi-scale molecular dynamics (MD) simulations to reveal the structural determinants of the human vault particle's flexibility. Cryo-EM identified two high-resolution alternative conformational states: a symmetric and an asymmetric structure, pointing to the vault shell's structural plasticity. MD simulations of these conformations revealed that these structures are flexible and exhibit breathing-like motions, and porous solvent-exposed surfaces. Mutagenesis disrupting persistent MD-identified inter-half contacts reduced full MVP shell assembly, confirming the functional relevance of these flexibility determinants. Together, these findings establish the molecular basis for the human vault particle's conformational plasticity.

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Publication Details

Journal
Nature Communications
Published
2026-05-02
DOI
https://doi.org/10.1038/s41467-026-72674-4
Primary Topic
Advanced Electron Microscopy Techniques and Applications
Type
article
Field-Weighted Citation Impact
0.00

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article

Structural flexibility of the human vault particle revealed by high-resolution cryo-EM and molecular dynamics simulations

Sonia Covaceuszach, Sergio Cruz-León, Alberto Cassetta, Fabio Lapenta et al.
Nature Communications
Advanced Electron Microscopy Techniques and Applications
article

Structural flexibility of the human vault particle revealed by high-resolution cryo-EM and molecular dynamics simulations

Sonia Covaceuszach, Sergio Cruz-León, Alberto Cassetta, Fabio Lapenta, Paolo Tortora, A Durand, Dihia Moussaoui, Jana Aupič, N. Marechal, Giulia Tomaino, Cristian Parra, Claudia D’Ercole, Bhavani Gangupam, Davide Cotugno, Simone Marrancone, Alessandra Magistrato, Gerhard Hummer, Karen Palacio-Rodriguez, Ario de Marco
article en

Abstract

Vaults are massive ribonucleoprotein complexes, highly conserved and abundant in eukaryotic cells, yet with unclear function. Their thin-walled barrel-shape architecture is composed of two symmetrical, antiparallel half-shells, each containing 39 copies of the major vault protein (MVP). The spacious lumen of the vault suggests a role in cellular transport. Although vaults are thought to undergo conformational changes to facilitate cargo exchange, the molecular basis for their inherent flexibility remains unknown. Here, we integrate cryogenic electron microscopy (cryo-EM) and multi-scale molecular dynamics (MD) simulations to reveal the structural determinants of the human vault particle's flexibility. Cryo-EM identified two high-resolution alternative conformational states: a symmetric and an asymmetric structure, pointing to the vault shell's structural plasticity. MD simulations of these conformations revealed that these structures are flexible and exhibit breathing-like motions, and porous solvent-exposed surfaces. Mutagenesis disrupting persistent MD-identified inter-half contacts reduced full MVP shell assembly, confirming the functional relevance of these flexibility determinants. Together, these findings establish the molecular basis for the human vault particle's conformational plasticity.

Nature Communications
Goethe University Frankfurt (DE), University of Nova Gorica (SI), AREA Science Park (IT), European Synchrotron Radiation Facility (FR), Universidad de Antioquia (CO), Institut de génétique et de biologie moléculaire et cellulaire (FR), Istituto Officina dei Materiali (IT), European Molecular Biology Laboratory (FR), Max Planck Institute of Biophysics (DE), European Institute of Oncology (IT), University of Milano-Bicocca (IT), International Centre for Genetic Engineering and Biotechnology (IT)
Javna Agencija za Raziskovalno Dejavnost RS, Fondazione Italiana per la Ricerca sul Cancro
Openalex Percentile: Top 9%
Advanced Electron Microscopy Techniques and Applications
DOIOpen Access PDFOpenAlex
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