2.D.1 The PI4P/PS Counter Transporter (P/P-CT) Family 

Lipid transfer between cell membrane bilayers at contacts between the endoplasmic reticulum (ER) and other membranes help to maintain membrane lipid homeostasis. Two similar ER integral membrane proteins, oxysterol-binding protein (OSBP)-related protein 5 (ORP5) and ORP8, tethered the ER to the plasma membrane (PM) via the interaction of their pleckstrin homology domains with phosphatidylinositol 4-phosphate (PI4P) in this membrane. Their OSBP-related domains (ORDs) harbored either PI4P or phosphatidylserine (PS) and exchanged these lipids between bilayers. Gain- and loss-of-function experiments showed that ORP5 and ORP8 could mediate PI4P/PS countertransport between the ER and the PM, thus delivering PI4P to the ER-localized PI4P phosphatase Sac1 for degradation and PS from the ER to the PM. This exchange helps to control plasma membrane PI4P levels and selectively enrich PS in the PM (Chung et al. 2015).

In eukaryotic cells, PS is synthesized in the ER but is highly enriched in the PM where it contributes negative charge and specific recruitment of signaling proteins. This distribution relies on transport mechanisms involving the yeast PS transporter Osh6p extracting phosphatidylinositol 4-phosphate (PI4P) and exchanging PS for PI4P between the two membranes. The crystal structure of Osh6p:PI4P complex has been solved (Moser von Filseck et al. 2015).and the transport of PS by Osh6p depends on PI4P recognition in vivo. The PI4P-phosphatase Sac1p, maintains a PI4P gradient at the ER/PM interface, to drive PS transport. Thus, PS transport by oxysterol-binding protein-related protein (ORP)/oxysterol-binding homology (Osh) proteins is fueled by PI4P metabolism through PS/PI4P exchange cycles.


 

References:

Chung, J., F. Torta, K. Masai, L. Lucast, H. Czapla, L.B. Tanner, P. Narayanaswamy, M.R. Wenk, F. Nakatsu, and P. De Camilli. (2015). INTRACELLULAR TRANSPORT. PI4P/phosphatidylserine countertransport at ORP5- and ORP8-mediated ER-plasma membrane contacts. Science 349: 428-432.

Du, X., J. Kumar, C. Ferguson, T.A. Schulz, Y.S. Ong, W. Hong, W.A. Prinz, R.G. Parton, A.J. Brown, and H. Yang. (2011). A role for oxysterol-binding protein-related protein 5 in endosomal cholesterol trafficking. J. Cell Biol. 192: 121-135.

Gehin, C., M.A. Lone, W. Lee, L. Capolupo, S. Ho, A.M. Adeyemi, E.H. Gerkes, A.P. Stegmann, E. López-Martín, E. Bermejo-Sánchez, B. Martínez-Delgado, C. Zweier, C. Kraus, B. Popp, V. Strehlow, D. Gräfe, I. Knerr, E.R. Jones, S. Zamuner, L.A. Abriata, V. Kunnathully, B.E. Moeller, A. Vocat, S. Rommelaere, J.P. Bocquete, E. Ruchti, G. Limoni, M. Van Campenhoudt, S. Bourgeat, P. Henklein, C. Gilissen, B.W. van Bon, R. Pfundt, M.H. Willemsen, J.H. Schieving, E. Leonardi, F. Soli, A. Murgia, H. Guo, Q. Zhang, K. Xia, C.R. Fagerberg, C.P. Beier, M.J. Larsen, I. Valenzuela, P. Fernández-Álvarez, S. Xiong, R. Śmigiel, V. López-González, L. Armengol, M. Morleo, A. Selicorni, A. Torella, M. Blyth, N.S. Cooper, V. Wilson, R. Oegema, Y. Herenger, A. Garde, A.L. Bruel, F. Tran Mau-Them, A.B. Maddocks, J.M. Bain, M.A. Bhat, G. Costain, P. Kannu, A. Marwaha, N.L. Champaigne, M.J. Friez, E.B. Richardson, V.K. Gowda, V.M. Srinivasan, Y. Gupta, T.Y. Lim, S. Sanna-Cherchi, B. Lemaitre, T. Yamaji, K. Hanada, J.E. Burke, A.M. Jakšić, B.D. McCabe, P. De Los Rios, T. Hornemann, G. D''Angelo, and V.A. Gennarino. (2023). CERT1 mutations perturb human development by disrupting sphingolipid homeostasis. J Clin Invest. [Epub: Ahead of Print]

Moser von Filseck, J., A. Čopič, V. Delfosse, S. Vanni, C.L. Jackson, W. Bourguet, and G. Drin. (2015). INTRACELLULAR TRANSPORT. Phosphatidylserine transport by ORP/Osh proteins is driven by phosphatidylinositol 4-phosphate. Science 349: 432-436.

Suchanek, M., R. Hynynen, G. Wohlfahrt, M. Lehto, M. Johansson, H. Saarinen, A. Radzikowska, C. Thiele, and V.M. Olkkonen. (2007). The mammalian oxysterol-binding protein-related proteins (ORPs) bind 25-hydroxycholesterol in an evolutionarily conserved pocket. Biochem. J. 405: 473-480.

Wu, Y., L. Min, P. Zhang, L. Zhang, Y. Xu, D. Li, M. Zheng, D. Pei, and Q. Wang. (2023). ORP5 promotes migration and invasion of cervical cancer cells by inhibiting endoplasmic reticulum stress. Cell Stress Chaperones. [Epub: Ahead of Print]

Examples:

TC#NameOrganismal TypeExample
2.D.1.1.1

Oxysterol binding protein-related, Orp5 of 879 aas and 1 C-terminal TMS. May cooperate with NPC1 to mediate the exit of cholesterol from endosomes/lysosomes (Du et al. 2011). Binds 25-hydroxycholesterol and cholesterol (Suchanek et al. 2007).  Catalyzes phosphatidyl-inositol-4-P (PI4P)/phosphatidyl serine (PS) exchange between the ER and the PM (Chung et al. 2015). ORP5 promotes migration and invasion of cervical cancer cells by inhibiting endoplasmic reticulum stress (Wu et al. 2023). It may therefore be a ER stress chaparone.

 

Animals

Orp5 of Homo sapiens

 
2.D.1.1.10

Ceramide transfer protein, CERT1, of 624 aas and possibly one TMS at residue position 250. Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability. Gehin et al. 2023 characterized missense variants in CERT1, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease (CerTra syndrome). Thus, CERT autoregulates the controls of the sphingolipid biosynthetic flux and provides insight into the structural organisation of CERT (Gehin et al. 2023).

CERT1 of Homo sapiens

 
2.D.1.1.2

Oxysterol binding protein-related, Orp8 protein of 889 aas and 1 C-terminal TMS in the ER membrane. May cooperate with NPC1 to mediate the exit of cholesterol from endosomes/lysosomes (Du et al. 2011). Binds 25-hydroxycholesterol and cholesterol (Suchanek et al. 2007).  Catalyzes phosphatidyl-inositol-4-P (PI4P)/phosphatidyl serine (PS) exchange between the ER and the PM (Chung et al. 2015).

Orp8 of Homo sapiens

 
2.D.1.1.3

Oxysterol binding protein of 448 aas with an N-terminal moderately hydrophobin sterol binding PH domain, Osh6.  Mediates phosphatidyl serine/phosphatidyl inositol 4-P exchange between the PM and ER (Moser von Filseck et al. 2015).

Osh6 of Saccharomyces cerevisiae

 
2.D.1.1.4

Oxysterol binding protein of 437 aas and 1 C-terminal TMS, Osh7, with a moderately hydrophobic N-terminal sterol binding PH domain.  Mediates phosphatidyl serine/phsophatidyl inositol 4-P exchange between the PM and ER (Moser von Filseck et al. 2015).

Osh7 of Saccharomyces cereviseae

 
2.D.1.1.5

Plant Orp4A protein of 386 aas and 0 TMSs.

Orp4A of Arabidopsis thaliana

 
2.D.1.1.6

Oxysterol binding-like 3 protein of 983 aas. 

Oxysterol binding protein of Fusarium oxysporum f. sp. cubense (Panama disease fungus)

 
2.D.1.1.7

Oxysterol bindiing protein of 432 aas.

Oxysterol binding protein of Acanthamoeba castellanii

 
2.D.1.1.8

Uncharacterized protein of 881 aas.

UP of Paramecium tetraurelia

 
2.D.1.1.9

Oxysterol binding protein of 784 aas.

Oxysterol binding protein of Drosophila melanogaster