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)