The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Accession:
Functional site class:
FFAT motif
Functional site description:
The FFAT motif binds to the Major Sperm Protein (MSP) domain of the integral Endoplasmic Reticulum (ER) membrane proteins Vesicle Associated Membrane Protein (VAMP) Associated Proteins, VAP-A and VAP-B. This motif was initially linked to the targeting of lipid trafficking and lipid sensing proteins to the cytosolic face of the ER. Further studies indicate that VAP-FFAT binding plays a part in the formation of membrane contact sites between the ER and other cellular membranes. Most known instances of FFAT motifs occur in mammal and yeast proteins but additional examples have been reported in pathogenic bacterial and viral proteins. VAP-FFAT interactions may play a role in disease etiology, as mutations in VAP-B have been implicated in late onset Spinal Muscular Atrophy and Amyotrophic Lateral Sclerosis – type 8. Another protein, MOSPD2, which also has an MSP domain has been identified as a second binding partner for FFAT proteins.
ELMs with same func. site: TRG_ER_FFAT_1  TRG_ER_FFAT_2 
ELM Description:
This class of motifs is similar to the classic FFAT motifs in many aspects, including the interaction with the VAP and MOSPD-2 proteins as well as the conservation of a phenylalanine or tyrosine residue in the second position. However, the major defining factor for this class is a serine or threonine residue replacing the aspartic acid at the fourth position of the original FFAT motif. In a number of instances, the amino acid in this position is phosphorylated (Kirmiz,2018, Christensen,2010). Additionally, these motifs tolerate much more variation in the first position as compared to the original FFAT class, suggesting that they could interact with their binding partners in a different way. As of the time of this annotation, no structure of this class of FFAT motifs binding to their partners has been published.
Pattern: [EDS].{0,4}[EDSQN][FY][FYMITH]([ST])[ACP].{1,2}[EDST]
Pattern Probability: 0.0000382
Present in taxons: Opisthokonta Viruses
Interaction Domain:
Motile_Sperm (PF00635) MSP (Major sperm protein) domain (Stochiometry: 1 : 1)
o See 7 Instances for TRG_ER_FFAT_2
o Abstract
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).
o 13 selected references:

o 7 GO-Terms:

o 7 Instances for TRG_ER_FFAT_2
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
O84008 CT_005
Y005_CHLTR
261 269 ESSSSSSFHTPPNSDKELSD TP 7 Chlamydia trachomatis D/UW-3/CX
Q14849 STARD3
STAR3_HUMAN
204 213 SGALSEGQFYSPPESFAGSD TP 8 Homo sapiens (Human)
2 
Q8TDY2 RB1CC1
RBCC1_HUMAN
727 738 SLAESPESDFMSAVNEFVIE TP 3 Homo sapiens (Human)
1 
Q80J95 Polyprotein
Q80J95_9CALI
44 52 SESEDEINYMTPPEQEAQPG TP 4 Murine norovirus 1
A6H8H5 Kcnb2
KCNB2_MOUSE
604 612 STSSIDSFTSCATDFTETER TP 3 Mus musculus (House mouse)
1 
Q03717 Kcnb1
KCNB1_MOUSE
589 597 SMSSIDSFISCATDFPEATR TP 7 Mus musculus (House mouse)
1 
O95772 STARD3NL
STR3N_HUMAN
205 214 PGGLSDGQFYSPPESEAGSE TP 14 Homo sapiens (Human)
3 
Please cite: The eukaryotic linear motif resource - 2018 update. (PMID:29136216)

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