Di Mattia, T;
Martinet, A;
Ikhlef, S;
McEwen, AG;
Nominé, Y;
Wendling, C;
Poussin‐Courmontagne, P;
... Alpy, F; + view all
(2020)
FFAT motif phosphorylation controls formation and lipid transfer function of inter‐organelle contacts.
The EMBO Journal
, Article e104369. 10.15252/embj.2019104369.
(In press).
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Abstract
Organelles are physically connected in 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 non‐conventional 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 create 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.
| Type: | Article |
|---|---|
| Title: | FFAT motif phosphorylation controls formation and lipid transfer function of inter‐organelle contacts |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.15252/embj.2019104369 |
| Publisher version: | https://doi.org/10.15252/embj.2019104369 |
| Language: | English |
| Additional information: | Copyright © 2020 The Authors. Published under the terms of the CC BY NC ND 4.0 license. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
| Keywords: | cholesterol, inter‐organelle contact, lipid transfer protein, regulation, small linear motif |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10113802 |
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