Specific refolding pathway of viscumin A chain in membrane-like medium reveals a possible mechanism of toxin entry into cell

How is a water-soluble globular protein able to spontaneously cross a cellular membrane? It is commonly accepted that it undergoes significant structural rearrangements on the lipid-water interface, thus acquiring membrane binding and penetration ability. In this study molecular dynamics (MD) simula...

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Bibliographic Details
Published in:Scientific reports 2019-01, Vol.9 (1), p.413-413, Article 413
Main Authors: Volynsky, Pavel E, Nolde, Dmitry E, Zakharova, Galina S, Palmer, Rex A, Tonevitsky, Alexander G, Efremov, Roman G
Format: Article
Language:English
Subjects:
Cell membranes
Chloroform
Epitopes
Hydrophobicity
Molecular dynamics
Protein structure
Proteins
Secondary structure
Urea
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Summary:How is a water-soluble globular protein able to spontaneously cross a cellular membrane? It is commonly accepted that it undergoes significant structural rearrangements on the lipid-water interface, thus acquiring membrane binding and penetration ability. In this study molecular dynamics (MD) simulations have been used to explore large-scale conformational changes of the globular viscumin A chain in a complex environment - comprising urea and chloroform/methanol (CHCl /MeOH) mixture. Being well-packed in aqueous solution, viscumin A undergoes global structural rearrangements in both organic media. In urea, the protein is "swelling" and gradually loses its long-distance contacts, thus resembling the "molten globule" state. In CHCl /MeOH, viscumin A is in effect turned "inside out". This is accompanied with strengthening of the secondary structure and surface exposure of hydrophobic epitopes originally buried inside the globule. Resulting solvent-adapted models were further subjected to Monte Carlo simulations with an implicit hydrophobic slab membrane. In contrast to only a few point surface contacts in water and two short regions with weak protein-lipid interactions in urea, MD-derived structures in CHCl /MeOH reveal multiple determinants of membrane interaction. Consequently it is now possible to propose a specific pathway for the structural adaptation of viscumin A with respect to the cell membrane - a probable first step of its translocation into cytoplasmic targets.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-018-36310-6