The lysosomal cystine transporter (LCT) family (TC# 2.A.43) is part of the TOG Superfamily and includes secondary transport proteins that are derived from animals, plants, fungi and other eukaryotes. They exhibit 7 putative transmembrane α-helical spanners (TMSs) and vary in size between about 200 and 500 amino acyl residues, although most have between 300 and 400 residues.[1]
These proteins are found in intracellular organelles of eukaryotes, many in lysosomes. The few that have been characterized transport Cystine (TC# 2.A.43.1.1), basic amino acids such as L-lysine and L-arginine (TC# 2.A.43.2.1) and drugs such as fluconazole and caspofungin (TC# 2.A.43.2.7).
Cystinosin edit
A protein mutated in the rare human genetic disease, nephropathic intermediate cystinosis,[2][3] also called cystinosin (TC# 2.A.43.1.1), is encoded by the CTNS gene. In cystinotic renal proximal tubules (RPTs), diminished cystinosin function appears to result in reduced reabsorption of solutes by other secondary transporters such as the Na+/Phosphate cotransporter, due to decreased expression of these other transport proteins.[1][4]
Function edit
Evidence suggests that cystinosin transports cystine out of lysosomes in a pmf-dependent process.[1] The proton motive force (pmf) across the lysosomal membrane is generated by a V-type ATPase which hydrolyzes cytoplasmic ATP to pump protons into the lysosomal lumen.[5] 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.[6] The cells then take up cystine in a pmf-dependent process.
Homologues edit
Distant homologues include the Lec15/Lec35 suppressor, SL15, of Chinese hamster ovary cells [7] and ERS1, the ERD suppressor in S. cerevisiae.[8] 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.[7] All proteins in the LCT family are distantly related to the proteins of the microbial rhodopsin (MR) family (TC #3.E.1),[3][9][10] an established member of the TOG Superfamily, which exhibit a 7 TMS topology.[1]
Reaction edit
The reaction believed to be catalyzed by cystinosin is:[1]
- Cystine (intralysosomal space) + H+ (intralysosomal space) → Cystine (cytoplasm) + H+ (cytoplasm)
References edit
- ^ a b c d e Saier, Milton. "Transporter Classification Database: 2.A.43 The Lysosomal Cystine Transporter (LCT) Family". tcdb.org. Retrieved 4 January 2016.
- ^ Theone, J; Lemons, R; Anikster, Y; Mullet, J; Paelicke, K; Lucero, C; Gahl, W; Schneider, J; Shu, SG; Campbell, HT (August 1999). "Mutations of CTNS causing intermediate cystinosis". Molecular Genetics and Metabolism. 67 (4): 283–93. doi:10.1006/mgme.1999.2876. PMID 10444339.
- ^ a b Zhai, Y; Heijne, WH; Smith, DW; Saier, MH Jr. (April 2, 2001). "Homologues of archaeal rhodopsins in plants, animals and fungi: structural and functional predications for a putative fungal chaperone protein". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1511 (2): 206–23. doi:10.1016/s0005-2736(00)00389-8. PMID 11286964.
- ^ Taub, ML; Springate, JE; Cutuli, F (April 8, 2011). "Reduced phosphate transport in the renal proximal tubule cells in cystinosis is due to decreased expression of transporters rather than an energy defect". Biochemical and Biophysical Research Communications. 407 (2): 355–9. doi:10.1016/j.bbrc.2011.03.022. PMID 21392501.
- ^ Smith, ML; Greene, AA; Potashnik, R; Mendoza, SA; Schneider, JA (January 25, 1987). "Lysosomal cystine transport. Effect of intralysosomal pH and membrane potential". The Journal of Biological Chemistry. 262 (3): 1244–53. doi:10.1016/S0021-9258(19)75778-0. PMID 2948955.
- ^ Kalatzis, V; Cherqui, S; Antignac, C; Gasnier, B (November 1, 2001). "Cystinosin, the protein defective in cystinosis, is a H(+)-driven lysosomal cystine transporter". EMBO J. 20 (21): 5940–9. doi:10.1093/emboj/20.21.5940. PMC 125690. PMID 11689434.
- ^ a b Ware, FE; Lehrman, MA (June 14, 1996). "Expression cloning of a novel suppressor of the Lec15 and Lec35 glycosylation mutations of Chinese hamster ovary cells". The Journal of Biological Chemistry. 271 (24): 13935–8. doi:10.1074/jbc.271.24.13935. PMID 8663248.
- ^ Hardwick, KG; Pelham, HR (April 25, 1990). "ERS1 a seven transmembrane domain protein from Saccharomyces cerevisiae". Nucleic Acids Res. 18 (8): 2177. doi:10.1093/nar/18.8.2177. PMC 330704. PMID 2186379.
- ^ Bieszke, JA; Braun, EL; Bean, LE; Kang, S; Natvig, DO; Borkovich, KA (July 6, 1999). "The nop-1 gene of Neurospora crassa encodes a seven transmembrane helix retinal-binding protein homologous to archaeal rhodopsins". Proceedings of the National Academy of Sciences USA. 96 (14): 8034–9. doi:10.1073/pnas.96.14.8034. PMC 22183. PMID 10393943.
- ^ Graul, RC; Sadee, W (November 1997). "Evolutionary relationships among proteins probed by an iterative neighborhood cluster analysis (INCA). Alignment of bacteriorhodopsins with the yeast sequence YRO2". Pharm. Res. 14 (11): 1533–41. doi:10.1023/a:1012166015402. PMID 9434271. S2CID 22648283.
