Human VAPome Analysis Reveals MOSPD1 and MOSPD3 as Membrane Contact Site Proteins Interacting with FFAT-Related FFNT Motifs

Membrane contact sites (MCS) are intracellular regions where two organelles come closer to exchange information and material. The majority of the endoplasmic reticulum (ER) MCS are attributed to the ER-localized tether proteins VAPA, VAPB, and MOSPD2. These recruit other proteins to the ER by intera...

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Published in:Cell reports (Cambridge) 2020-12, Vol.33 (10), p.108475-108475, Article 108475
Main Authors: Cabukusta, Birol, Berlin, Ilana, van Elsland, Daphne M., Forkink, Iris, Spits, Menno, de Jong, Anja W.M., Akkermans, Jimmy J.L.L., Wijdeven, Ruud H.M., Janssen, George M.C., van Veelen, Peter A., Neefjes, Jacques
Format: Article
Language:English
Subjects:
Amino Acid Motifs - genetics
Cell Line
Cell Line, Tumor
Cell Membrane - metabolism
Cell Membrane - physiology
Emery-Dreifuss muscular dystrophy
endoplasmic reticulum
Endoplasmic Reticulum - genetics
Endoplasmic Reticulum - metabolism
FFAT
FFNT
Humans
Intracellular Signaling Peptides and Proteins - metabolism
Intracellular Signaling Peptides and Proteins - physiology
membrane contact sites
Membrane Proteins - metabolism
Membrane Proteins - physiology
Mitochondrial Membranes - metabolism
MOSPD1
MOSPD2
MOSPD3
Protein Binding - genetics
Protein Interaction Domains and Motifs - genetics
Protein Interaction Domains and Motifs - physiology
Protein Interaction Mapping - methods
VAPA
VAPB
Vesicular Transport Proteins - metabolism
Vesicular Transport Proteins - physiology
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Summary:Membrane contact sites (MCS) are intracellular regions where two organelles come closer to exchange information and material. The majority of the endoplasmic reticulum (ER) MCS are attributed to the ER-localized tether proteins VAPA, VAPB, and MOSPD2. These recruit other proteins to the ER by interacting with their FFAT motifs. Here, we describe MOSPD1 and MOSPD3 as ER-localized tethers interacting with FFAT motif-containing proteins. Using BioID, we identify proteins interacting with VAP and MOSPD proteins and find that MOSPD1 and MOSPD3 prefer unconventional FFAT-related FFNT (two phenylalanines [FF] in a neutral tract) motifs. Moreover, VAPA/VAPB/MOSPD2 and MOSPD1/MOSPD3 assemble into two separate ER-resident complexes to interact with FFAT and FFNT motifs, respectively. Because of their ability to interact with FFNT motifs, MOSPD1 and MOSPD3 could form MCS between the ER and other organelles. Collectively, these findings expand the VAP family of proteins and highlight two separate complexes in control of interactions between intracellular compartments. [Display omitted] •MOSPD1 and MOSPD3 contain functional MSP domains to interact with short linear motifs•Instead of FFAT motifs, MOSPD1 and MOSPD3 prefer FFAT-related FFNT motifs•FFAT-binding proteins and FFNT-binding proteins form two separate ER-resident complexes•By interacting with FFNT motifs, MOSPD1 and MOSPD3 can form membrane contact sites Cabukusta et al. characterize MOSPD1 and MOSPD3 as members of the ER-resident VAP protein family interacting with short linear motif. Unlike VAPA, VAPB, and MOSPD2, MOSPD1 and MOSPD3 do not interact with canonical FFAT motifs but prefer unconventional motifs related to FFAT or FFNT motifs.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2020.108475