TRG_ER_FFAT_1

The FFAT (diphenylalanine [FF] in an acidic tract) targets cytosolic proteins to the surface/periphery of the endoplasmic reticulum (ER) (Loewen,2003) and the nuclear envelope (NE), a subcompartment of the ER (Brickner,2004). The ER is involved in a wide range of different biological processes and functions (Baumann,2001). In particular, the lumen and membrane of the ER provide a path for secreted and integral membrane proteins and lipids to reach their target compartments, complete with appropriate post-translational modifications. The cytosolic surface of the ER is associated with extensive lipid biosynthesis, and a range of peripheral membrane proteins are specifically targeted to this surface (Baumann,2001).
The FFAT (diphenylalanine [FF] in an acidic tract) motif was initially identified as a short sequence shared between a set of proteins targeted to the ER cytosolic side. In further definition of the function, the motif was shown to mediate interactions with yeast members of the VAP protein family (Loewen,2003). FFAT motifs have been shown to interact with the major sperm protein (MSP) domains of Mammalia and Saccharomyces cerevisiae members of the VAP family of type II integral endoplasmic reticulum proteins (Lev,2008) (luminal C-terminus and cytosolic N-terminus). The 3D structure of the MSP domain-FFAT motif (rat VAP-A with rat ORP1) interaction has been solved using X-ray crystallography (1Z9O) (Kaiser,2005). This interaction is mediated by a positive patch on the MSP domain surface, which is conserved (e.g. in Saccharomyces cerevisiae, Arabidopsis thaliana, Caenorhabditis elegans, Homo sapiens, and Schizosaccharomyces pombe) 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.