SLC66 Lysosomal amino acid transporters | Transporters

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SLC superfamily of solute carriers
SLC66 Lysosomal amino acid transporters

SLC66 Lysosomal amino acid transporters C

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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This is a family of 5 evolutionarily related proteins. Their structural similarities suggest that they are transporters. Biochemical evidence supports transporter activity for SLC66A1 (LAAT1) and SLC66A4 (CTNS; Cystinosin), primarily exporting amino acids from the lysosome to the cytoplasm. The functions of the 3 remaining members of the family are undetermined.

Transporters

3161

solute carrier family 66 member 1 / SLC66A1 C Show summary »« Hide summary

Target Id	3160
Nomenclature	solute carrier family 66 member 1
Systematic nomenclature	SLC66A1
Previous and unofficial names	LAAT-1 \| LAAT1 \| lysosomal amino acid transporter 1 homolog \| PQLC2 \| PQ loop repeat containing 2
Genes	SLC66A1 (Hs), Slc66a1 (Mm), Slc66a1 (Rn)
Ensembl ID	ENSG00000040487 (Hs), ENSMUSG00000028744 (Mm), ENSRNOG00000017706 (Rn)
UniProtKB AC	Q6ZP29 (Hs), Q8C4N4 (Mm), B0BMY1 (Rn)
Comment	Responsible for lysine and arginine export from lysosomes [7]. Functions as a pH-sensitive uniporter [6]. Transports cysteamine-cysteine mixed disulfide, structurally similar to lysine, which is a chemical intermediate formed during cysteamine therapy of cystinosis [3]. Acts to recruit the C9orf72-SMCR8-WDR41 complex to the cytoplasmic side of the lysosome upon cationic amino acid starvation, as the initiator of the signaling cascade [1,10].

solute carrier family 66 member 2 / SLC66A2 C Show summary »« Hide summary

Target Id	3161
Nomenclature	solute carrier family 66 member 2
Systematic nomenclature	SLC66A2
Previous and unofficial names	PQLC1 \| PQ loop repeat containing 1
Genes	SLC66A2 (Hs), Slc66a2 (Mm), Slc66a2 (Rn)
Ensembl ID	ENSG00000122490 (Hs), ENSMUSG00000034006 (Mm), ENSRNOG00000059215 (Rn)
UniProtKB AC	Q8N2U9 (Hs), Q80XM9 (Mm), Q5M880 (Rn)

solute carrier family 66 member 3 / SLC66A3 C Show summary »« Hide summary

Target Id	3162
Nomenclature	solute carrier family 66 member 3
Systematic nomenclature	SLC66A3
Previous and unofficial names	Pqlc3 \| PQ loop repeat containing \| PQLC3 \| PQ loop repeat containing 3
Genes	SLC66A3 (Hs), Slc66a3 (Mm), Slc66a3 (Rn)
Ensembl ID	ENSG00000162976 (Hs), ENSMUSG00000045679 (Mm), ENSRNOG00000005126 (Rn)
UniProtKB AC	Q8N755 (Hs), Q8C6U2 (Mm)

cystinosin, lysosomal cystine transporter / SLC66A4 C Show summary »« Hide summary

Target Id	3163
Nomenclature	cystinosin, lysosomal cystine transporter
Systematic nomenclature	SLC66A4
Previous and unofficial names	cystinosin \| CTNS-LSB \| cystinosis, nephropathic \| PQLC4
Genes	CTNS (Hs), Ctns (Mm), Ctns (Rn)
Ensembl ID	ENSG00000040531 (Hs), ENSMUSG00000005949 (Mm), ENSRNOG00000028688 (Rn)
UniProtKB AC	O60931 (Hs), P57757 (Mm)
Comment	Exports cystine (cysteine disulfide) from the lysosomes into the cytoplasm. Acts as a cystine/H⁺ symporter at a 1:1 stiochiometry [8]. Loss of function causes the monogenic systemic disease cystinosis [4,11], characterized by intra-lysosomal cystine accumulation in all body cells and organs [2].

mannose-P-dolichol utilization defect 1 / SLC66A5 C Show summary »« Hide summary

Target Id	3164
Nomenclature	mannose-P-dolichol utilization defect 1
Systematic nomenclature	SLC66A5
Previous and unofficial names	Lec35 \| PQLC5 \| SL15
Genes	MPDU1 (Hs), Mpdu1 (Mm), Mpdu1 (Rn)
Ensembl ID	ENSG00000129255 (Hs), ENSMUSG00000018761 (Mm), ENSRNOG00000012162 (Rn)
UniProtKB AC	O75352 (Hs)
Comment	MPDU1 mutations cause congenital disorder of glycosylation type If (CDG-If) [5,9].

References

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1. Amick J, Tharkeshwar AK, Talaia G, Ferguson SM. (2020) PQLC2 recruits the C9orf72 complex to lysosomes in response to cationic amino acid starvation. J Cell Biol, 219 (1). [PMID:31851326]

2. Elmonem MA, Veys KR, Soliman NA, van Dyck M, van den Heuvel LP, Levtchenko E. (2016) Cystinosis: a review. Orphanet J Rare Dis, 11: 47. [PMID:27102039]

3. Jézégou A, Llinares E, Anne C, Kieffer-Jaquinod S, O'Regan S, Aupetit J, Chabli A, Sagné C, Debacker C, Chadefaux-Vekemans B et al.. (2012) Heptahelical protein PQLC2 is a lysosomal cationic amino acid exporter underlying the action of cysteamine in cystinosis therapy. Proc Natl Acad Sci U S A, 109 (50): E3434-43. [PMID:23169667]

4. Kalatzis V, Cherqui S, Antignac C, Gasnier B. (2001) Cystinosin, the protein defective in cystinosis, is a H(+)-driven lysosomal cystine transporter. EMBO J, 20 (21): 5940-9. [PMID:11689434]

5. Kranz C, Denecke J, Lehrman MA, Ray S, Kienz P, Kreissel G, Sagi D, Peter-Katalinic J, Freeze HH, Schmid T et al.. (2001) A mutation in the human MPDU1 gene causes congenital disorder of glycosylation type If (CDG-If). J Clin Invest, 108 (11): 1613-9. [PMID:11733556]

6. Leray X, Conti R, Li Y, Debacker C, Castelli F, Fenaille F, Zdebik AA, Pusch M, Gasnier B. (2021) Arginine-selective modulation of the lysosomal transporter PQLC2 through a gate-tuning mechanism. Proc Natl Acad Sci U S A, 118 (32). [PMID:34344826]

7. Liu B, Du H, Rutkowski R, Gartner A, Wang X. (2012) LAAT-1 is the lysosomal lysine/arginine transporter that maintains amino acid homeostasis. Science, 337 (6092): 351-4. [PMID:22822152]

8. Ruivo R, Bellenchi GC, Chen X, Zifarelli G, Sagné C, Debacker C, Pusch M, Supplisson S, Gasnier B. (2012) Mechanism of proton/substrate coupling in the heptahelical lysosomal transporter cystinosin. Proc Natl Acad Sci U S A, 109 (5): E210-7. [PMID:22232659]

9. Schenk B, Imbach T, Frank CG, Grubenmann CE, Raymond GV, Hurvitz H, Korn-Lubetzki I, Revel-Vik S, Raas-Rotschild A, Luder AS et al.. (2001) MPDU1 mutations underlie a novel human congenital disorder of glycosylation, designated type If. J Clin Invest, 108 (11): 1687-95. [PMID:11733564]

10. Talaia G, Amick J, Ferguson SM. (2021) Receptor-like role for PQLC2 amino acid transporter in the lysosomal sensing of cationic amino acids. Proc Natl Acad Sci U S A, 118 (8). [PMID:33597295]

11. Town M, Jean G, Cherqui S, Attard M, Forestier L, Whitmore SA, Callen DF, Gribouval O, Broyer M, Bates GP et al.. (1998) A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis. Nat Genet, 18 (4): 319-24. [PMID:9537412]

NC-IUPHAR subcommittee and family contributors

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Database page citation (select format):

Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Fabbro D, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: Transporters. Br J Pharmacol. 180 Suppl 2:S374-469.

SLC66 Lysosomal amino acid transporters C

Overview

Transporters

Further reading

References

NC-IUPHAR subcommittee and family contributors

How to cite this family page