2.A.43 The Lysosomal Cystine Transporter (LCT) Family

The LCT family includes proteins that are derived from animals, plants and fungi. They exhibit 7 putative transmembrane α-helical spanners (TMSs) and vary in size between 247 and 487 amino acyl residues although most have between 300 and 400 residues. One of the animal proteins is the lysosomal cystine transporter of humans, also called cystinosin, encoded by the CTNS gene. Mutations in this protein cause nephropathic intermediate cystinosis (Thoene et al., 1999; Zhai et al., 2001). In cystinotic renal proximal tubules (RPTs), defects in cystinosin function results in reduced reabsorption of solutes by apical Na+ solute cotransport systems, including the Na+/Phosphate cotransport system, due to decreased expression of the other transporters (Taub et al., 2011).

Evidence suggests that cystinosin transports cystine out of lysosomes in a pmf-dependent process. The pmf across the lysosomal membrane is generated by a V-type ATPase which hydrolyzes cytoplasmic ATP to pump protons into the lysosomal lumen (Smith et al., 1987). Removal of the C-terminal GYDQL lysosomal sorting motif causes cystinosin to migrate to the plasma membrane with the intralysosomal face of cystinosin facing the extracellular medium (Kalatzis et al., 2001). The cells then take up cystine in a pmf-dependent process.

Distant homologues include the Lec15/Lec35 suppressor, SL15, of Chinese hamster ovary cells (Ware and Lehrman, 1996) and ERS1, the ERD suppressor in S. cerevisiae (Hardwick and Pelham, 1990). Both of these suppressors, when overexpressed, have been reported to influence retention of lumenal endoplasmic reticular proteins as well as glycosylation in the Golgi apparatus. The Lec15 and Lec35 mutations are characterized by inefficient synthesis and utilization, respectively, of mannose-P-dolichol for glycolipid biosynthesis (Ware and Lehrman, 1996). All of these proteins are distantly related to the proteins of the microbial rhodopsin (MR) family (TC #3.E.1) (Bieszke et al., 1999; Graul and Sadee, 1999; Zhai et al., 2001) which exhibit an established 7 TMS topology.

The reaction believed to be catalyzed by cystinosin is:

Cystine (intralysosomal space) + H+ (intralysosomal space)  Cystine (cytoplasm) + H+ (cytoplasm)

This family belongs to the Transporter-Opsin-G protein-coupled receptor (TOG) Superfamily.



Bieszke, J.A., E.L. Brauir, L.E. Bean, S. Kang, D.O. Natvig, and K.A. Borkovich. (1999). The nop-1 gene of Neurospora crassa encodes a seven transmembrane helix retinal-binding protein homologous to aracheal rhodopsins. Evolution 96: 8034-8039.

Gao, X.D., J. Wang, S. Keppler-Ross, and N. Dean. (2005). ERS1 encodes a functional homologue of the human lysosomal cystine transporter. FEBS J. 272: 2497-2511.

Graul, R.C. and W. Sadee. (1997). Evolutionary relationships among proteins by an iterative neighborhood cluster analysis (INCA). Alignment of bacteriorhodopsin with the yeast sequence YRO2. Pharm. Res. 11: 1533-1541.

Hardwick, K.G. and H.R.B. Pelham. (1990). ERS1 a seven transmembrane domain protein from Saccharomyces cerevisiae. Nucleic Acids Res. 18: 2177.

Jézégou, A., E. Llinares, C. Anne, S. Kieffer-Jaquinod, S. O'Regan, J. Aupetit, A. Chabli, C. Sagné, C. Debacker, B. Chadefaux-Vekemans, A. Journet, B. André, and B. Gasnier. (2012). Heptahelical protein PQLC2 is a lysosomal cationic amino acid exporter underlying the action of cysteamine in cystinosis therapy. Proc. Natl. Acad. Sci. USA 109: E3434-3443.

Kalatzis, V., S. Cherqui, C. Antignac, and B. Gasnier. (2001). Cystinosin, the protein defective in cystinosis, is a H(+)-driven lysosomal cystine transporter. EMBO J. 20: 5940-5949.

Liu, B., H. Du, R. Rutkowski, A. Gartner, and X. Wang. (2012). LAAT-1 is the lysosomal lysine/arginine transporter that maintains amino acid homeostasis. Science 337: 351-354.

Ruivo, R., G.C. Bellenchi, X. Chen, G. Zifarelli, C. Sagné, C. Debacker, M. Pusch, S. Supplisson, and B. Gasnier. (2012). Mechanism of proton/substrate coupling in the heptahelical lysosomal transporter cystinosin. Proc. Natl. Acad. Sci. USA 109: E210-217.

Smith, M.L., A.A. Greene, R. Potashnik, S.A. Mendoza, and J.A. Schneider. (1987). Lysosomal cystine transport. J. Biol. Chem. 262: 1244-1253.

Taub, M.L., J.E. Springate, and F. Cutuli. (2011). Reduced phosphate transport in the renal proximal tubule cells in cystinosis is due to decreased expression of transporters rather than an energy defect. Biochem. Biophys. Res. Commun. 407: 355-359.

Thoene, J., R. Lemons, Y. Anikster, J. Mullet, K. Paelicke, C. Lucero, W. Gahl, J. Schneider, S.G. Shu, and T. Campbell. (1999). Mutations of CTNS causing intermediate cystinosis. Mol. Genet. Metabol. 67: 283-293.

Ware, F.E. and M.A. Lehrman. (1996). Expression cloning of a novel suppressor of the Lec15 and Lec35 glycosylation mutations of Chinese hamster ovary cells. J. Biol. Chem. 271: 13935-13938.

Yamamoto, T., K. Fujimura-Kamada, E. Shioji, R. Suzuki, and K. Tanaka. (2017). Cfs1p, a Novel Membrane Protein in the PQ-Loop Family, Is Involved in Phospholipid Flippase Functions in Yeast. G3 (Bethesda) 7: 179-192.

Zhai, Y., W.H.M. Heijne, D.W. Smith, and M.H. Saier, Jr. (2001). Homologues of archaeal rhodopsins in plants, animals and fungi: structural and functional predications for a putative fungal chaperone protein. Biochim. Biophys. Acta 1511: 206-223.


TC#NameOrganismal TypeExample

Lysosomal cystine transporter, cystinosin. Uses a cystine:H+ symport mechanism. H+ binds to an aspartate residue in one of the two PQ-loops (Ruivo et al., 2012).

Animals (homologues in plants and fungi)

Cystinosin of Homo sapiens

2.A.43.1.2Cystinosin homologAnimalsCG17119 of Drosophila melanogaster

The ERD-1 suppressor, ERS1


ERS1 of Saccharomyces cerevisiae (P17261)

2.A.43.1.4Cystinosin homologPlantsAt5g40670 of Arabidopsis thaliana

TC#NameOrganismal TypeExample

The lysosomal lysine-arginine transporter, LAAT1 or PQ-loop repeat containing protein 2 (PQLC2) (291aas; 7 TMSs). Also transports the mixed disulfide of cysteine-cysteamine, a lysine analogue, as well as canavanine, a toxic arginine analogue. Cysteamine is used in the treatment of cystinosis (Liu et al., 2012; Jézégou et al. 2012).


PQLC2 of Homo sapiens (Q6ZP29)


The probable vacuolar amino acid transporter YPQ1 of 381 aas and 6 TMSs.

Ypq1 of Sesamum indicum


The probable vacuolar amino acid transporter Ypq1 of 381 aas and 6 TMSs

Ypq1 of Gossypium raimondii].


Uncharacterized protein of 282 aas and 7 (3 + 4) TMSs.

UP of Gossypium raimondii


Cdc50 supressor, CSF1 of 405 aas and 7 TMSs.  Appears to function as a phospholipid flippase or to regulate PL flipping in endosomes or late golgi vesicles (Yamamoto et al. 2017).

CSF1 of Saccharomyces cerevisiae


Uncharacterized PQ loop repeat protein of 228 aas and 6 TMSs.

UP of Entamoeba histolytica


The lysosomal lysine-arginine transporter, LAAT1, PQ-loop superfamily member (qx42 gene product; 310aas; 7 TMSs) (Liu et al., 2012).


LAAT1 of Caenorhabditis elegans (Q95XZ6)


Vacuolar (lysosomal) cationic amino acid transporter (YOL092W) (308aas; 7 TMSs), LAAT1.  Involved in cationic amino acid homeostasis (Jézégou et al. 2012).


LAAT1 of Saccharomyces cerevisiae (Q12010)


PQ-loop repeat protein (320aas; 7 TMSs)


PQLR protein Entamoeba histolyticus (C4LT11)


PQ-loop repeat protein (288aas; 7 TMSs)


 PQLR protein of Arabidopsis thaliana (O49437)


7 TMS protein 1 (319aas; 7 TMSs)


7 TMS protein of Giardia lamblia (E1F7I8)


Probable vacuolar (lysosomal) cationic amino acid exporter, RTC2 (Ypq3; Ybr147). Involved in amino acid homeostasis. Up-regulated by addition of ammonia or amino acids to a nitrogen-depleted medium (Jézégou et al. 2012). Resistant to fluconazole. Increased resistance to caspofungin. Suppresses CDC13-1 temperature sensitivity.


RTC2 of Saccharomyces cerevisiae


Vacuolar (lysosomal) putative cationic amino acid exporter, Ypq2 (Ydr352); involved with cationic amino acid homeostasis (Jézégou et al. 2012).


Ypq2 of Saccharomyces cerevisiae


PQ loop protein of 384 aas and 7 (3 + 4) TMSs

PQ-loop protein of Populus trichcarpa


TC#NameOrganismal TypeExample
2.A.43.3.1The Lec15/Lec35 suppressor, SL15 Animals SL15 of Cricetulus griseus

PQ-loop-containing protein 3 (PQLC3)


PQLC3 of Mus musculus (Q8C6U2)


TC#NameOrganismal TypeExample
2.A.43.4.1Uncharacterized protein C4C5.03YeastSPAC4C5.03 of Schizosaccharomyces pombe

Uncharacteerized protein of 308 aas and 7 TMSs.

UP of Entamoeba histolytica


Uncharacterized protein of 363 aas and 8 TMSs.

UP of Entamoeba histolytica