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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)

References associated with 2.A.43 family:

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. 10393943
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. 15885099
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. 9434271
Hardwick, K.G. and H.R.B. Pelham. (1990). ERS1 a seven transmembrane domain protein from Saccharomyces cerevisiae. Nucleic Acids Res. 18: 2177. 2186379
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. 23169667
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. 11689434
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. 22822152
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. 22232659
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. 2948955
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. 21392501
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. 10444339
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. 8663248
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. 11286964