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PreprintCited by 4Mitochondrial Function and PathologyProtein Structure and DynamicsLipid Membrane Structure and Behavior

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Lys716 in the transmembrane domain of yeast mitofusin Fzo1 modulates anchoring and fusion

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Versini, Raphaëlle, Baaden, Marc, Cavellini, Laetitia, Cohen, Mickaël M., Taly, Antoine, Fuchs, Patrick F.J.·2023·Structure
DOI 10.1101/2023.09.22.559002

Preprint — published as 10.1016/j.str.2024.08.017 · Paper page

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Abstract

Outer mitochondrial membrane (OMM) fusion is an important process for the cell and organism survival, as its dysfunction is linked to neurodegenerative diseases and cancer. The OMM fusion is mediated by members of the dynamin-related protein (DRP) family, named mitofusins. The exact mechanism by which the mitofusins contribute to these diseases, as well as the exact molecular fusion mechanism mediated by mitofusin, remains elusive. We have performed extensive multiscale molecular dynamics simulations using both coarse-grained and all-atom approaches to predict the dimerization of two transmembrane domain (TM) helices of the yeast mitofusin Fzo1. We identify specific residues, such as Lys716, that can modulate dimer stability. Comparison with a previous computational model reveals remarkable differences in helix crossing angles and interfacial contacts. Overall, however, the TM1-TM2 interface appears to be stable in the Martini and CHARMM force fields. Replica-exchange simulations further tune a detailed atomistic model, as confirmed by a remarkable agreement with an independent prediction of the Fzo1-Ugo1 complex by AlphaFold2. Functional implications, including a possible role of Lys716 that could affect membrane interactions during fusion, are suggested and consistent with experiments monitoring mitochondrial respiration of selected Fzo1 mutants.

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Metadata

Authors
Versini, R., Baaden, M., Cavellini, L., Cohen, M. M., Taly, A., & Fuchs, P. F. J.
Affiliations
Centre National de la Recherche Scientifique (FR)
Corresponding author
  • Taly, Antoine
  • Fuchs, Patrick F.J.
ORCID
Venue
Structure
Publisher
openRxiv
Published
2023-09-22
Volume
32
Issue
11
Pages
1997-2012.e7
ISSN
0969-2126 (ISSN-L)
DOI
10.1101/2023.09.22.559002
OpenAlex
W4402597829
Cited by
4
References
1
Citations by year
2026: 1 · 2025: 1 · 2024: 2
FWCI
0.55
Type
journal article
Language
en
Open access
Locations
  • Structure (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
Funders
  • Agence Nationale de la Recherche (ANR‐19, ANR-19-CE11-0018, ANR-11-LABX-0011)
  • Grand Équipement National De Calcul Intensif
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
Keywords
mitofusins, Fzo1, transmembrane domain, membrane perturbation, protein-protein complex, yeast
MeSH terms
Protein Domains, Lysine, Membrane Fusion, Membrane Proteins, Protein Binding, Saccharomyces cerevisiae, GTP Phosphohydrolases, Mitochondrial Proteins, Saccharomyces cerevisiae Proteins, Mitochondrial Membranes, Molecular Dynamics Simulation, Mitochondrial Dynamics

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