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Journal Articles EMBO Journal Year : 2020

FFAT motif phosphorylation controls formation and lipid transfer function of inter‐organelle contacts

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Abstract

Organelles are physically connected by membrane contact sites. The endoplasmic reticulum possesses three major receptors, VAP-A, VAP-B, and MOSPD2, which interact with proteins at the surface of other organelles to build contacts. VAP-A, VAP-B, and MOSPD2 contain an MSP domain, which binds a motif named FFAT (two phenylalanines in an acidic tract). In this study, we identified a non-conventional FFAT motif where a conserved acidic residue is replaced by a serine/threonine. We show that phosphorylation of this serine/threonine is critical for nonconventional FFAT motifs (named Phospho-FFAT) to be recognized by the MSP domain. Moreover, structural analyses of the MSP domain alone or in complex with conventional and Phospho-FFAT peptides revealed new mechanisms of interaction. Based on these new insights, we produced a novel prediction algorithm, which expands the repertoire of candidate proteins with a Phospho-FFAT that are able to form membrane contact sites. Using a prototypical tethering complex made by STARD3 and VAP, we showed that phosphorylation is instrumental for the formation of ER-endosome contacts, and their sterol transfer function. This study reveals that phosphorylation acts as a general switch for inter-organelle contacts.
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Origin : Publication funded by an institution

Dates and versions

hal-03045974 , version 1 (08-12-2020)

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Thomas Di Mattia, Arthur Martinet, Souade Ikhlef, Alastair G Mcewen, Yves Nominé, et al.. FFAT motif phosphorylation controls formation and lipid transfer function of inter‐organelle contacts. EMBO Journal, 2020, 39 (23), ⟨10.15252/embj.2019104369⟩. ⟨hal-03045974⟩
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