FFAT

FFAT stands for two phenylalanines in an acidic tract. It is a short linear sequence motif found in cytosolic regions of proteins that target the endoplasmic reticulum (ER) by binding to VAP proteins on the ER membrane. The canonical consensus is often described as EFFDAxE, with two phenylalanines embedded in an acidic environment; variants known as FFAT-like motifs also occur.

The motif mediates tethering between the ER and other organelles, enabling the formation of membrane contact sites (MCSs). Through interaction with VAP A or VAP B, FFAT-containing proteins recruit lipid transfer proteins to ER membranes, facilitating non-vesicular lipid transport and coordination of lipid metabolism and signaling at these contact sites.

Examples of FFAT-containing proteins include the ceramide transfer protein (CERT) and several members of the OSBP/ORP family, as well as other ER–organelle tethers. The presence of FFAT motifs is widespread in eukaryotes and supports ER-directed localization of proteins involved in lipid trafficking and signaling at ER–Golgi, ER–mitochondria, and ER–peroxisome contacts.

Variations exist in FFAT motifs, and flanking acidic residues influence binding affinity. Some proteins harbor FFAT-like motifs with substitutions that can modulate interaction strength. Regulation of FFAT–VAP interactions can occur through post-translational modifications or conformational changes, impacting the dynamics of membrane contact sites and lipid homeostasis.

Discovery and context: FFAT motifs were identified as key determinants of ER targeting and lipid transfer at membrane contact sites, highlighting their role in coordinating inter-organelle lipid exchange. See also: VAP proteins, membrane contact sites, lipid transfer proteins.