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

Subra, M.; Dezi, M.; Bigay, J.; Lacas-Gervais, S.; Di Cicco, A.; Dias Araujo, A. R.; Abelanet, S.; Fleuriot, L.; Debayle, D.; Gautier, R.; Patel, A.; Roussi, F.; Antonny, B.; Levy, D.; Mesmin, B.

doi:10.1101/2022.05.13.491839

bioRxiv · 10.1101/2022.05.13.491839

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

Subra, M.·Dezi, M.·Bigay, J.·Lacas-Gervais, S.·Di Cicco, A.·Dias Araujo, A. R.·Abelanet, S.·Fleuriot, L.·Debayle, D.·Gautier, R.·Patel, A.·Roussi, F.·Antonny, B.·Levy, D.·Mesmin, B.

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Abstract

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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Subra, M., Dezi, M., Bigay, J., Lacas-Gervais, S., Di Cicco, A., Dias Araujo, A. R., Abelanet, S., Fleuriot, L., Debayle, D., Gautier, R., Patel, A., Roussi, F., Antonny, B., Levy, D., Mesmin, B.. 2022-05-13. VAP-A intrinsically disordered regions enable versatile tethering at membrane contact sites. https://doi.org/10.1101/2022.05.13.491839

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