title: VAP, a Versatile Access Point for the Endoplasmic Reticulum: Review and analysis of FFAT-like motifs in the VAPome.
abstract: Dysfunction of VAMP-associated protein (VAP) is associated with neurodegeneration, both Amyotrophic Lateral Sclerosis and Parkinson's disease. Here we summarize what is known about the intracellular interactions of VAP in humans and model organisms. VAP is a simple, small and highly conserved protein on the cytoplasmic face of the endoplasmic reticulum (ER). It is the sole protein on that large organelle that acts as a receptor for cytoplasmic proteins. This may explain the extremely wide range of interacting partners of VAP, with components of many cellular pathways binding it to access the ER. Many proteins that bind VAP also target other intracellular membranes, so VAP is a component of multiple molecular bridges at membrane contact sites between the ER and other organelles. So far approximately 100 proteins have been identified in the VAP interactome (VAPome), of which a small minority have a "two phenylalanines in an acidic tract" (FFAT) motif as it was originally defined. We have analyzed the entire VAPome in humans and yeast using a simple algorithm that identifies many more FFAT-like motifs. We show that approximately 50% of the VAPome binds directly or indirectly via the VAP-FFAT interaction. We also review evidence on pathogenesis in genetic disorders of VAP, which appear to arise from reduced overall VAP levels, leading to ER stress. It is not possible to identify one single interaction that underlies disease. This article is part of a Special Issue entitled: The cellular lipid landscape edited by Tim P. Levine and Anant K. Menon.
authors.affiliation: Department of Cell Biology, UCL Institute of Ophthalmology, 11-43 Bath Street, UK EC1V 9EL.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Murphy
authors.affiliation: Department of Cell Biology, UCL Institute of Ophthalmology, 11-43 Bath Street, UK EC1V 9EL. Electronic address: tim.levine@ucl.ac.uk.
authors.forename: Tim P
authors.initials: TP
authors.lastname: Levine
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs / Q000502:physiology*; D060066:Protein Interaction Maps; D033921:Vesicular Transport Proteins / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*
chemical_list: C114051:VAPA protein, human; C496748:VAPB protein, human; D033921:Vesicular Transport Proteins
keywords: Amyotrophic Lateral Sclerosis/genetics; Biological Transport; Endoplasmic Reticulum/*metabolism; Intracellular Membranes/*metabolism; Motor Neurons/*metabolism; Vesicular Transport Proteins/genetics/*metabolism