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PreprintCited by 4Cellular transport and secretionLipid Membrane Structure and BehaviorProtein Structure and Dynamics

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VAP-A intrinsically disordered regions enable versatile tethering at membrane contact sites

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Subra, Mélody, Dezi, Manuela, Bigay, Joëlle, Lacas-Gervais, Sandra, Di Cicco, Aurélie, Dias Araújo, Ana Rita, Abélanet, Sophie, Fleuriot, Lucile, Debayle, Delphine, Gautier, Romain, Patel, Amanda, Roussi, Fanny, Antonny, Bruno, Lévy, Daniel, Mesmin, Bruno·2022·bioRxiv (Cold Spring Harbor Laboratory)
DOI 10.1101/2022.05.13.491839

Preprint — published as 10.1016/j.devcel.2022.12.010

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Abstract

SUMMARY: Membrane contact sites (MCSs) between organelles are heterogeneous in shape, composition and dynamics. Despite this diversity, VAP proteins act as receptors for multiple FFAT motif-containing proteins and drive the formation of most MCSs involving the endoplasmic reticulum (ER). Although the VAP‒FFAT interaction is well characterized, no model explains how VAP adapts to its partners in various MCSs. We report here that VAP-A localization to different MCSs depends on its intrinsically disordered regions (IDRs). We show that VAP-A interaction with PTPIP51 and VPS13A at ER‒mitochondria MCS conditions mitochondria fusion by promoting lipid transfer and cardiolipin buildup. VAP-A also enables lipid exchange at ER‒Golgi MCS by interacting with OSBP and CERT. However, removing IDRs from VAP-A restricts its distribution and function to ER‒ mitochondria MCS, at the expense of ER‒Golgi MCS. Our data suggest that IDRs of VAP-A do not modulate its preference towards specific partners, but adjust its geometry to the constraints linked to different MCS organization and lifetime. Thus, VAP-A conformational flexibility mediated by its IDRs ensures membrane tethering plasticity and efficiency.

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Metadata

Authors
Subra, M., Dezi, M., Bigay, J., Lacas-Gervais, S., Di Cicco, A., Dias Araújo, A. R., Abélanet, S., Fleuriot, L., Debayle, D., Gautier, R., Patel, A., Roussi, F., Antonny, B., Lévy, D., & Mesmin, B.
Affiliations
Centre National de la Recherche Scientifique (FR)
Corresponding author
Mesmin, Bruno
ORCID
Venue
bioRxiv (Cold Spring Harbor Laboratory)
Publisher
openRxiv
Published
2022-05-13
DOI
10.1101/2022.05.13.491839
OpenAlex
W4280650616
Cited by
4
References
3
Citations by year
2025: 1 · 2024: 1 · 2023: 1 · 2022: 1
Type
posted content
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • theses.fr (ABES) (submittedVersion, other-oa)
  • HAL (submittedVersion, other-oa)
Funders
  • Infrastructures en Biologie Santé et Agronomie (ANR-10-INBS-04)
  • Agence Nationale de la Recherche (10-INBS-04, ANR‐10_INBS‐04, ANR-10)
  • Centre National de la Recherche Scientifique (ANR-10-INBS-04)
  • Freie Universität Berlin
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
VAPA, intrinsically disordered regions, membrane contact sites, FFAT motif, endoplasmic reticulum, ER-mitochondria tethering, mitochondrial fusion, lipid transfer, cardiolipin, PTPIP51, VPS13A, oxysterol-binding protein, CERT, lipid exchange, protein flexibility

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