TRG_ER_FFAT_2

The Endoplasmic Reticulum (ER) is a dynamic structure that serves as a site of bulk membrane lipid biogenesis for most of the cell organelles with a major portion of lipid production being associated with the cytosolic leaflet of the ER membrane (Baumann,2001). Thus, many proteins with roles in lipid metabolism must access the ER surface. VAP proteins are ER membrane proteins that are highly conserved among eukaryotes, consisting of a C-terminal transmembrane domain, a flexible linker that may contain a short coiled coil, and a cytosolic N-terminal MSP domain (Lev,2008, PF00635). VAPs contribute to the targeting of proteins to the ER through the interaction that occurs between their MSP domain and the FFAT motif of various proteins in both mammals and yeast (Loewen,2003).

Many of the proteins that contain FFAT motifs function in lipid sensing and lipid exchange. Additionally, a role of VAPs in the formation of Membrane Contact Sites (MCSs) has emerged. MCSs are distinct domains between the ER and other organelles where organellar membranes are bridged by proteins (often with a gap less than 30 nm), but do not fuse. MCSs have been proposed to facilitate the non-vesicular trafficking of small molecules, such as lipids (Helle,2013). VAP-FFAT interactions have been shown to control the formation of MCSs between the ER and other cellular membranes, including the plasma membrane, mitochondria, late endosomes, peroxisomes and vesicles that contain uptaken, possibly pathogenic, bacteria.

The 3D structure of the MSP domain-FFAT motif (rat VAP-A with rat ORP1) interaction has been solved using X-ray crystallography (1Z9O). This interaction is mediated by a positive patch on the MSP domain surface, which is strongly conserved (e.g. in Saccharomyces cerevisiae, Schizosaccharomyces pombe, Arabidopsis thaliana, Caenorhabditis elegans and Homo sapiens) in the VAP-family MSP domains, but not in other MSP domains (Loewen,2005). The crystal structure reveals an unusual cooperatively assembled dimer of dimers in a “double peptide sandwich” conformation. FFAT motifs can also bind VAPs as monomers, as was revealed by a more recently obtained solution structure for VAP-A with the FFAT of OSBP (2RR3).