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

Cell Rep. 2020 Dec 8;33(10):108475. doi: 10.1016/j.celrep.2020.108475.

Abstract

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.

Keywords: Emery-Dreifuss muscular dystrophy; FFAT; FFNT; MOSPD1; MOSPD2; MOSPD3; VAPA; VAPB; endoplasmic reticulum; membrane contact sites.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs / genetics
  • Cell Line
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Cell Membrane / physiology
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Intracellular Signaling Peptides and Proteins / physiology
  • Membrane Proteins / metabolism*
  • Membrane Proteins / physiology
  • Mitochondrial Membranes / metabolism
  • Protein Binding / genetics
  • Protein Interaction Domains and Motifs / genetics
  • Protein Interaction Domains and Motifs / physiology
  • Protein Interaction Mapping / methods
  • Vesicular Transport Proteins / metabolism*
  • Vesicular Transport Proteins / physiology

Substances

  • Intracellular Signaling Peptides and Proteins
  • MOSPD1 protein, human
  • Membrane Proteins
  • Vesicular Transport Proteins