The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Accession:
Functional site class:
FFAT motif
Functional site description:
The FFAT motif targets proteins to the cytosolic periphery of the ER via interaction with the MSP (major sperm protein) domain of members of the VAP family. Functional instances of the motif are known in mammals and yeast.
ELM Description:
The FFAT (diphenylalanine [FF] in an acidic tract) motif was initially identified as a short sequence shared between a set of ER-targeted proteins, that was shown to mediate interactions with yeast members of the VAP protein family (Loewen,2003). The consensus motif was initially described as EFFDAxE with one or more acidic residues within five residues upstream of this pattern. However, despite its name and this consensus description of the motif, functional instances of the motif are observed with tyrosine replacing either of the two phenylalanines (although there always seems to be at least one phenylalanine in the motif). Mammalian VAP proteins have been observed as dimers - in the crystal structure they form a 2:2 MSP-domain:FFAT-peptide complex. So far the yeast members of the family have not been observed as dimers. In the crystal structure, the side chain of the first phenylalanine residue of the motif binds in hydrophobic pocket on the surface of the MSP domain. The second phenylalanine residue forms polar contacts via the backbone to the MSP domain. Both motifs in the 2:2 complex interact with both MSP domains, while only one of the motif side chains (the D at the fourth position of the canonical consensus) interacts with the other peptide. One reported FFAT motif instance replaces the second F with a K (Saita,2009); perhaps this will affect its (hetero)dimerisation abilities? It is considered that most FFAT motifs have been identified in the mammalian and yeast lineages. However, if there are FFAT motifs in fission yeast or plants or other eukaryotic lineages, the motif will probably have diverged.
Pattern: [DE].{0,4}E[FY][FYK]D[AC].[ESTD]
Pattern Probability: 2.404e-07
Present in taxons: Homo sapiens Opisthokonta Rattus norvegicus Saccharomyces cerevisiae
Interaction Domain:
Motile_Sperm (PF00635) MSP (Major sperm protein) domain (Stochiometry: 1 : 1)
PDB Structure: 1Z9O
o See 20 Instances for TRG_ER_FFAT_1
o Abstract
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.
o 6 selected references:

o 5 GO-Terms:

o 20 Instances for TRG_ER_FFAT_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
Q5JSH3 WDR44
WDR44_HUMAN
4 15 MASESDTEEFYDAPEDVHLG U 1 Homo sapiens (Human)
Q709C8 VPS13C
VP13C_HUMAN
873 883 TVESESDDEYFDAEDGEPQT U 1 Homo sapiens (Human)
Q5T4F4 ZFYVE27
ZFY27_HUMAN
282 292 AEEAEPDEEFKDAIEETHLV TP 6 Homo sapiens (Human)
Q9BZ72 PITPNM2
PITM2_HUMAN
339 350 RDSDESSDDEFFDAHEDLSD TP 2 Homo sapiens (Human)
O00562 PITPNM1
PITM1_HUMAN
347 355 SENSSEEEFFDAHEGFSDSE TP 8 Homo sapiens (Human)
Q9BZ71 PITPNM3
PITM3_HUMAN
29 40 SDSVESSDDEFFDAREEMAE TP 2 Homo sapiens (Human)
Q5SYB0 FRMPD1
FRPD1_HUMAN
768 776 EDGSSDEEYYDAADKLTPPG U 1 Homo sapiens (Human)
Q9Y5P4 COL4A3BP
C43BP_HUMAN
319 327 NSLINEEEFFDAVEAALDRQ TP 2 Homo sapiens (Human)
P21957 OPI1
OPI1_YEAST
195 206 SSDEDDDDEEFFDASEQVNA TP 5 Saccharomyces cerevisiae (Baker"s yeast)
P22059 OSBP
OSBP1_HUMAN
353 364 DMSDEDDENEFFDAPEIITM TP 5 Homo sapiens (Human)
Q96SU4 OSBPL9
OSBL9_HUMAN
292 300 SYSSSEDEFYDADEFHQSGS TP 5 Homo sapiens (Human)
Q9BZF2 OSBPL7
OSBL7_HUMAN
398 408 LSLADSHTEFFDACEVLLSA TP 1 Homo sapiens (Human)
Q9BZF3 OSBPL6
OSBL6_HUMAN
490 500 LSMSESVSEFFDAQEVLLSA TP 3 Homo sapiens (Human)
Q969R2 OSBP2
OSBP2_HUMAN
446 457 EDSEEDEDTEYFDAMEDSTS TP 1 Homo sapiens (Human)
Q9H4L5 OSBPL3
OSBL3_HUMAN
446 456 LSITDSLSEFFDAQEVLLSP TP 5 Homo sapiens (Human)
Q9H1P3 OSBPL2
OSBL2_HUMAN
4 12 MNGEEEFFDAVTGFDSDNSS TP 1 Homo sapiens (Human)
Q8K4M9 Osbpl1a
OSBL1_RAT
473 481 VSILSEDEFYDALSGSESEG TP 1 Rattus norvegicus (Norway rat)
P38713 OSH3
OSH3_YEAST
511 520 TSYLSENDEFFDAEEEISRG TP 3 Saccharomyces cerevisiae (Baker"s yeast)
Q12451 OSH2
OSH2_YEAST
742 751 EDEASDADEFYDAAELVDEV TP 3 Saccharomyces cerevisiae (Baker"s yeast)
P35845 SWH1
OSH1_YEAST
711 722 ESDEDSDADEFFDAEEAASD TP 3 Saccharomyces cerevisiae (Baker"s yeast)
Please cite: ELM 2016-data update and new functionality of the eukaryotic linear motif resource. (PMID:26615199)

ELM data can be downloaded & distributed for non-commercial use according to the ELM Software License Agreement