6TQS

The crystal structure of the MSP domain of human MOSPD2 in complex with the conventional FFAT motif of ORP1.

Summary for 6TQS

• Entry DOI: 10.2210/pdb6tqs/pdb
• Descriptor: Motile sperm domain-containing protein 2, Oxysterol-binding protein-related protein 1, GLYCEROL, ... (9 entities in total)
• Functional Keywords: membrane contact sites, ffat motif, msp domain, endoplasmic reticulum, protein binding
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 11
• Total formula weight: 159233.47

Authors

McEwen, A.G.,Poussin-Courmontagne, P.,Di Mattia, T.,Wendling, C.,Cavarelli, J.,Tomasetto, C.,Alpy, F. (deposition date: 2019-12-17, release date: 2020-11-18, Last modification date: 2024-01-24)

Primary citation

Di Mattia, T.,Martinet, A.,Ikhlef, S.,McEwen, A.G.,Nomine, Y.,Wendling, C.,Poussin-Courmontagne, P.,Voilquin, L.,Eberling, P.,Ruffenach, F.,Cavarelli, J.,Slee, J.,Levine, T.P.,Drin, G.,Tomasetto, C.,Alpy, F.
FFAT motif phosphorylation controls formation and lipid transfer function of inter-organelle contacts.
Embo J., 39:e104369-e104369, 2020

PubMed 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.

PubMed: 33124732
DOI: 10.15252/embj.2019104369

Experimental method

X-RAY DIFFRACTION (2.25 Å)