TABLE 1.
An overview of experimentally confirmed VAP binding partners in mammalian cells.
| Complex | Interaction domain | Localisation a | MCS | Physiological role of the VAP complex | Reference | |
|---|---|---|---|---|---|---|
| Binding partner | VAP | |||||
| ACBD4-VAPB | FFAT motif (score 3.5) | MSP | Peroxisomes (TMD) | Peroxisome-ER | Organelle tethering function | Costello et al. (2017b), |
| 173RDLDSE VFCDS—LE QL | Kors et al. (2022) | |||||
| ACBD5-VAPA/B | FFAT motif (score 2.5) | MSP | Peroxisomes (TMD) | Peroxisome-ER | Organelle tethering function, implicated in: peroxisome motility; peroxisome membrane expansion; plasmalogen synthesis; maintenance of cholesterol levels | Costello et al. (2017a), |
| 259SDSDSE VYCDS—ME QF | Hua et al. (2017) | |||||
| α-Synuclein-VAPB | ? | MSP | Cytosol, nucleus, membranes | Disrupts the PTPIP51-VAPB interaction, hence mitochondria-ER MCS (affecting Ca2+ exchange) | Paillusson et al. (2017) | |
| ASNA1-VAPA/B | FFAT motif (score 2.0) | MSP | Cytosol, ER, nucleus | Mediating interaction with the transmembrane-domain recognition complex (TRC; insertion of tail anchored ER proteins) | Baron et al. (2014) | |
| 8WGVEAE EFEDAPD VE | ||||||
| ATF6-VAPA/B | ? | MSP | ER (TMD), nucleus (cleaved) | Modulates the activity of ATF6-regulated transcription of genes involved in the unfolded protein response (UPR) | Gkogkas et al. (2008) | |
| CALCOCO1-VAPA/B | FFAT-motif (score 3.0) | MSP | Nucleus, cytosol | Autophagosome-ER | Acts as ER-phagy receptor for degradation of the tubular ER, via ATG8 interaction | Nthiga et al. (2020) |
| 674DHMDGH FFFS——T—QD PF | ||||||
| CaSR-VAPA | FFAT motif (score 2.5) b | MSP | Plasma membrane (TMD) | Plasma membrane-ER | Ca2+ sensing; near surface CaSR expression | Gorkhali et al. (2021) |
| 755ELEDEI IFIT——CHE GS | ||||||
| CERT-VAPA/B | FFAT motif (score 1.0) | MSP | Cytosol, Golgi (PH domain) | Golgi-ER | Ceramide transfer from the ER to the Golgi apparatus, for sphingomyelin synthesis | Kawano et al. (2006), |
| 315SLINEE EFFDAVE AA | Saito et al. (2008), | |||||
| Kumagai et al. (2014) | ||||||
| CLN8-VAPA | ? | ? | ER (TMD), ER-Golgi intermediate compartment (ERGIC; TMD) | Possibly: Ceramide metabolism; endo-lysosomal dynamics | Passantino et al. (2013), | |
| Adhikari et al. (2019), | ||||||
| Pesaola et al. (2021) | ||||||
| CDIP1-VAPA/B | FFAT motif (score 6.0) | MSP | Endocytic compartments (MMD) | CDIP1-induced cell death | Inukai et al. (2021) | |
| 180IPCLIN DFKDVTH TC | ||||||
| FAF1-VAPA/B | FFAT motif (score 1.0) | MSP | Nucleus, cytosol | Binding of ubiquitinated proteins; recruiting p97 to the ER membrane (involved in ER-associated protein degradation (ERAD)) | Baron et al. (2014) | |
| 289SDSDGD DFEDATE FG | ||||||
| FAPP1-VAPA/B | C-terminus | ? | Golgi (PH domain) | Golgi-ER | Formation of the SAC1-FAPP1-VAP complex – binding of FAPP1 to the PI4P-phosphatase SAC1 promotes the phosphatase activity | Venditti et al. (2019) |
| FIP200-VAPA/B | FFAT motif 1 (score 3.0) | MSP | Cytosol, (pre-) autophagosomal structures, lysosomes, nucleus | Isolation membrane-ER | Formation/stabilization of the ULK1/FIP200-WIPI2 complex during isolation membrane expansion for autophagosome formation | Zhao et al. (2018) |
| 725AESPES DFMS——AVN EF | ||||||
| FFAT motif 2 (score 4.0) | ||||||
| 206ECLTRH SYRECLG RL | ||||||
| GLTP-VAPA | FFAT motif (score 3.5) | MSP | Cytosol | Possibly: Glycolipid transfer, glucosylceramide sensor | Tuuf et al. (2009), | |
| 26AVSHLP PFFDCLG SP | Backman et al. (2018) | |||||
| HCN2-VAPA/B | TMD | TMD | ER | Regulation of HCN channel Na+/K+ pacemaker currents; dendritic localization of HCN2 | Silbernagel et al. (2018) | |
| IFITM3-VAPA | TMD | TMD and CC | Endosomes, lysosomes, plasma membrane | Preventing the VAPA-OSBP association, which induces cholesterol accumulation, inhibiting viral entry | Amini-Bavil-Olyaee et al. (2013) | |
| JMY-VAPA | FFAT motif (score 1.5) b | MSP | Nucleus, cytoskeleton | Possibly: Vesicle based transport | Schlüter et al. (2014) | |
| 312ETDDPE EYYES—LS EL | ||||||
| Kv2.1-VAPA/B | FFAT motif (score 3.5) | MSP | Plasma membrane (TMD) | Plasma membrane-ER | Kv2 channel clustering; regulating proapoptotic K+ currents; phosphatidylinositol homeostasis (via NIR2 recruitment) | Johnson et al. (2018), |
| 584SMSSID SFIS——CAT DF | Kirmiz et al. (2018, 2019), | |||||
| Schulien et al. (2020) | ||||||
| Kv2.2-VAPA/B | FFAT motif (score 3.0) | MSP | Plasma membrane (TMD) | Plasma membrane-ER | Kv2 channel clustering | Johnson et al. (2018), |
| 599STSSID SFTS——CAT DF | Kirmiz et al. (2018) | |||||
| MIGA2-VAPA/B | FFAT motif (score 1.5) | MSP | Mitochondria (TMD), lipid droplets | Mitochondria-ER | Linking reactions of de novo lipogenesis in mitochondria to triglyceride production in the ER | Freyre et al. (2019) |
| 286SLTSED SFFS——ATE LF | ||||||
| NIR1-VAPB | FFAT motif (score 0.0) | MSP | Plasma membrane (LNS2 domain), cytosol | Plasma membrane-ER | Promoting NIR2 recruitment for phosphatidylinositol homeostasis | Amarilio et al. (2005), |
| 28VESSDD EFFDARE EM | Quintanilla et al. (2022) | |||||
| NIR2-VAPB | FFAT motif (score 0.0) | MSP | Golgi (LNS2 domain), plasma membrane (LNS2 domain), cytosol | Golgi-ER | Phosphatidylinositol transfer to the Golgi apparatus and phosphatidylcholine transfer to the ER (important for CERT and OSBP Golgi targeting/function) | Amarilio et al. (2005), |
| 343ENSSEE EFFDAHE GF | Plasma membrane-ER | Phosphatidylinositol transfer from the ER to the plasma membrane | Peretti et al. (2008),Chang et al. (2013),Chang and Liou (2015),Kirmiz et al. (2019) | |||
| NIR3-VAPB | FFAT motif (score 0.0) | MSP | Plasma membrane (LNS2 domain), cytosol | Plasma membrane-ER | Phosphatidylinositol transfer from the ER to the plasma membrane | Amarilio et al. (2005), |
| 338DESSDD EFFDAHE DL | Microtubule interaction | Chang and Liou, (2015) | ||||
| OSBP-VAPA | FFAT motif (score 0.0)352DEDDEN EFFDAPE II | MSP | Golgi (PH domain), endosomes (PH domain), lysosomes (PH domain), cytosol | Golgi-EREndosome-ERLysosome-ER | Cholesterol transfer from the ER to the Golgi apparatus in exchange for PI4PRegulation of PI4P levels on endosomesCholesterol transfer from the ER to lysosomes, regulating mTORC1 activation | Wyles et al. (2002),Loewen et al. (2003),Mesmin et al. (2013),Dong et al. (2016),Lim et al. (2019) |
| ORP1L-VAPA/B | FFAT motif (score 1.5) | MSP | Late endosomes/lysosomes (PH domain and ankyrin motif), autophagosome, phagolysosome | Late endosome/lysosome (LEL)-ER | Cholesterol transport from the LEL to the ER (high cholesterol) and vice versa (low cholesterol); endosome positioning | Rocha et al. (2009), |
| 469SILSED EFYDALS DS | Autophagosome-ER | Regulating autopagosome transport and maturation | Eden et al. (2016), | |||
| Phagolysosome-ER | PI4P transfer to the ER, for phagolysosome resolution | Wijdeven et al. (2016), | ||||
| Zhao and Ridgway (2017), | ||||||
| Levin-Konigsberg et al. (2019) | ||||||
| ORP2-VAPA | FFAT motif (score 1.5) | MSP | Lipid droplets, plasma membrane, cytosol | Lipid droplet-ER | Triglyceride metabolism | Weber-Boyvat et al. (2015b) |
| 1MNGEE EFFDAVT GF | ||||||
| ORP3-VAPA | FFAT motif 1 (score 1.0) | MSP | Plasma membrane (PH domain), cytosol | Plasma membrane-ER | Stimulating R-Ras signalling | Lehto et al. (2005), |
| 444ITDSLS EFFDAQE VL | Late endosome-nuclear envelope | The nuclear transfer of extracellular vesicle-derived materials | Weber-Boyvat et al. (2015a), | |||
| FFAT motif 2 (score 4.5) | Santos et al. (2018) | |||||
| 155FPHEVN HFFS——GST IT | ||||||
| ORP4L-VAPA | FFAT motif (score 0.0) | MSP | Golgi (PH domain), plasma membrane | Plasma membrane-ER c | Controlling the localization and activation of the phosphoinositide phospholipases C β3 (PLCβ3) at the plasma membrane | Pan et al. (2018), |
| 445EEDEDT EYFDAME DS | Golgi-ER | The maintenance of Golgi structure | Pietrangelo and Ridgway, (2018) | |||
| ORP6-VAP | FFAT motif (score 1.0) b | MSP | Plasma membrane (PH domain), cytosol | Plasma membrane-ER | PI4P turnover | Wyles and Ridgway (2004), |
| 488MSESVS EFFDAQE VL | Mochizuki et al. (2018) | |||||
| ORP7-VAP | FFAT motif (score 1.0) b | MSP | Plasma membrane (PH domain), cytosol | ? | Wyles and Ridgway (2004), | |
| 396LADSHT EFFDACE VL | Weber-Boyvat et al. (2015b) | |||||
| ORP9L-VAPA | FFAT motif (score 1.0) | MSP | Golgi (PH domain), cytosol | Golgi-ER | Golgi organization and protein transport; cholesterol transfer | Wyles and Ridgway (2004), |
| 294YSSSED EFYDADE FH | Ngo and Ridgway, (2009) | |||||
| PP2Cϵ-VAP | TMD | TMD | ER (TMD) | Dephosphorylating CERT, which promotes Golgi localisation of CERT and enhances the CERT-VAPA interaction | Saito et al. (2008) | |
| PRA1-VAP | FFAT motif (score 5.5) b | MSP | Golgi (TMD), ER (TMD) | Mitochondria-ER | ER retention of PRA1 | Abu Irqeba and Ogilvie, (2020) |
| 66RLVRNV EYYQS—NY VF | ||||||
| Prestin-VAPA | ? | ? | Plasma membrane (TMD) | Prestin translocation to the plasma membrane | Sengupta et al. (2010) | |
| Protrudin-VAPA/B | FFAT motif (score 1.0) | MSP, TMD | ER (TMD), endosomes (FYVE domain), plasma membrane (FYVE domain) | Endosome-ER | Endosome trafficking; stimulating process/neurite formation | Saita et al. (2009), |
| 280EAEPDE EFKDAIE ET | Matsuzaki et al. (2011), | |||||
| Raiborg et al. (2015), | ||||||
| Petrova et al. (2020) | ||||||
| PTPIP51-VAP | FFAT motif 1 (score 3.0) | MSP | Mitochondria (TMD) | Mitochondria-ER | Ca2+ delivery to mitochondria from ER stores, which regulates autophagy and synaptic function; phosphatidic acid transfer, important for mitochondrial cardiolipin synthesis | De Vos et al. (2012), |
| 151STGSSS VYFT——ASS GA | Stoica et al. (2014), | |||||
| FFAT motif 2 (score 3.5) | Gómez-Suaga et al. (2017), | |||||
| 160TASSGA TFTDAES EG | Gómez-Suaga et al. (2019), | |||||
| Yeo et al. (2021) | ||||||
| RAB3GAP1-VAPA/B | FFAT motif (score 0.5) | MSP | Cytosol | Regulating nuclear envelope formation through ERGIC | Baron et al. (2014), | |
| 578WSDSEE EFFECLS DT | Hantan et al. (2014) | |||||
| SCRN1-VAPA/B | FFAT motif (score 2.5) | MSP | Cytosol | Modulating Ca2+ homeostasis and synaptic vesicle cycling; ER dynamics | Lindhout et al. (2019) | |
| 394AEVGDL FYDCVD TE | ||||||
| SNX2- VAPB | FFAT motif 1 (score 3.5) | MSP | Endosomes (PX domain) | Endosome-ER | Retromer-/WASH-dependent actin nucleation (vesicle budding) of endosomes, with a role of PI4P (see OSBP) | Dong et al. (2016) |
| 21LEDGED LFTS——T—VS TL | ||||||
| FFAT motif 2 (score 2.0) | ||||||
| 66DDDRED LFAEATE EV | ||||||
| STARD3-VAPA/B | FFAT motif (score 5.5) | MSP | Late endosomes (TMD) | Late endosome-ER | Cholesterol transport from the ER to endosome | Alpy et al. (2013), |
| 200GALSEG QFYS——PPE SF | Wilhelm et al. (2017), | |||||
| Di Mattia et al. (2020) | ||||||
| STARD3NL-VAPA/B | FFAT motif (score 5.5) | MSP | Late endosomes (TMD) | Late endosome-ER | Formation of endosomal tubules | Alpy et al. (2013) |
| 201GGLSDG QFYS——PPE SE | ||||||
| TRPC3-VAPB | FFAT motif (score 5.0) | MSP | Plasma membrane | Plasma membrane-ER | Controls TRPC3’s Ca2+ current and its receptor-mediated activation | Liu et al. (2022) |
| 140QELQDD DFYAYDE DG | ||||||
| TTC39B-VAPB | FFAT motif (score 2.0) | MSP | Cytosol | Stabilizing ER-membrane protein SCAP, involved in hepatic lipogenic gene expression | Hsieh et al. (2021) | |
| 76LEADED VFEDALE TI | ||||||
| ULK1-VAPA/B | FFAT motif 1 (score 5.5) | MSP | Cytosol, pre-autophagosomal structures | Isolation membrane-ER | Formation/stabilization of the ULK1/FIP200-WIPI2 complex during isolation membrane expansion for autophagy | Zhao et al. (2018) |
| 87SVYLVM EYCNGGD LA | ||||||
| FFAT motif 2 (score 5.5) | ||||||
| 74NIVALY DFQEMAN SV | ||||||
| Viperin-VAPA | C-terminus | C-terminus | ER, lipid droplets | Restricting Hepatitis C virus replication complex formation by promoting degradation of viral NS5A through VAPA | Wang et al. (2012), | |
| Ghosh et al. (2020) | ||||||
| VPS13A-VAPA/B | FFAT motif (score 1.0) | MSP | Mitochondria (ATG homology region, PH domain), lipid droplets (PH domain) | Mitochondria-ER | Mitochondria elongation; glycerolipid transfer between membranes | Kumar et al. (2018), |
| 836EDDSEE EFFDAPC SP | Lipid droplet-ER | Lipid droplet size and motility; glycerolipid transfer between membranes | Yeshaw et al. (2019) | |||
| VPS13C-VAPB | FFAT motif (score 0.0) | MSP | Late endosomes/lysosomes (WD40 module), lipid droplets (PH domain) | Endolysosome-ER | Glycerolipid transfer between membranes | Kumar et al. (2018) |
| 871ESESDD EYFDAED GE | Lipid droplet-ER | Glycerolipid transfer between membranes | ||||
| VPS13D-VAPB | FFAT motif (score 5.0) | MSP | Golgi, mitochondria | Mitochondria-ER | Bridging the organelle membranes via MIRO at the mitochondrial membrane (likely similar with peroxisomes); membrane lipid transfer | Guillén-Samander et al. (2021) |
| 761TQFSDD EYKT——PLA TP | ||||||
| WDR44-VAPA/B | FFAT motif (score 0.5) | MSP | Cytosol, endosomes, Golgi | Tubular endosome formation and/or stabilization | Baron et al. (2014), | |
| 3SESDTE EFYDAPE DV | Häsler et al. (2020) | |||||
| YIF1A-VAPB | TMD | MSP | ER-Golgi intermediate compartment (ERGIC; TMD); ER (TMD), Golgi (TMD) | Controls the shuttling of YIF1A between the ERGIC and the ER; promotes intracellular membrane delivery into dendrites | Kuijpers et al. (2013b) | |
FFAT motif scores were calculated using the FFAT scoring algorithm (best FFAT motif scores zero) c (Murphy and Levine, 2016). Phosphorylation of serine/threonine at position 4 (double underlined) of the core (bold) of Phospho-FFAT motifs is critical for VAP binding (Di Mattia et al., 2020). Phosphorylation of serine/threonine at position 5 (underlined) of FFAT motifs abolishes VAP binding (Kors et al., 2022). The cellular localisations of the binding partners are listed. The physiological role describes the function of the VAP complex (binding partners may also have been implicated in other non-VAP related processes, or functions might not have been directly linked to VAP yet).
ACBD4/5, acyl-CoA-binding domain-containing protein 4/5; ASNA1 (TRC40), arsenite-stimulated ATPase; ATF6, activating transcription factor 6; CALCOCO1, calcium-binding and coiled-coil domain-containing protein 1; CaSR, calcium-sensing receptor; CERT, ceramide transfer protein; CLN8, ceroid-lipofuscinosis neuronal protein 8; CDIP1, cell death-inducing p53-target protein 1; FAF1, FAS-associated factor 1 (ubiquitin-binding protein); FAPP1, phosphatidylinositol-four-phosphate adapter protein 1; FIP200, FAK family kinase-interacting protein of 200 kDa; GLTP, glycolipid transfer protein; HCN2, hyperpolarization-activated cyclic nucleotide-gated channel 2; IFITM3, interferon-inducible transmembrane protein 3; JMY, junction-mediating and -regulatory protein; Kv2, potassium voltage-gated channel subfamily B; MCS, membrane contact site; MIGA2, mitoguardin 2; MMD, monotopic integral membrane domain; MSP, major sperm protein; NIR, PYK2 N-terminal domain-interacting receptor; ORP, oxysterol-binding protein-related protein; OSBP, oxysterol-binding protein; PP2Cϵ, protein phosphatase 2Cϵ; PRA1, prenylated Rab acceptor 1; PTPIP51, protein tyrosine phosphatase-interacting protein 51; RAB3GAP1, RAB3 GTPase-activating protein catalytic subunit; SCRN1, secernin-1; SNX2, sorting nexin-2; STARD3, StAR-related lipid transfer protein 3; STARD3NL, STARD3 N-terminal like; TMD, transmembrane domain; TRPC3, transient receptor potential channel 3; TTC39B, tetratricopeptide repeat domain containing protein 39 B; ULK1, UNC-51-like autophagy-activating kinase 1; Viperin, Virus inhibitory protein, endoplasmic reticulum-associated, interferon-inducible; VPS13, Vacuolar protein sorting-associated protein 13; WDR44, WD repeat-containing protein 44; YIF1A, YIP1-interacting factor homologue A.
a
Due to their interaction with VAP, the proteins also localise at the ER (ER is only mentioned if the protein contains another ER targeting domain, e.g. TMD).
b
Predicted FFAT motif, but not confirmed.
c
The FFAT score does not indicate the definite binding strength.