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Structure paper

TitleStructure and mechanism of human cystine exporter cystinosin.
Journal, issue, pagesCell, Vol. 185, Issue 20, Page 3739-3752.e18, Year 2022
Publish dateSep 29, 2022
AuthorsXue Guo / Philip Schmiege / Tufa E Assafa / Rong Wang / Yan Xu / Linda Donnelly / Michael Fine / Xiaodan Ni / Jiansen Jiang / Glenn Millhauser / Liang Feng / Xiaochun Li /
PubMed AbstractLysosomal amino acid efflux by proton-driven transporters is essential for lysosomal homeostasis, amino acid recycling, mTOR signaling, and maintaining lysosomal pH. To unravel the mechanisms of ...Lysosomal amino acid efflux by proton-driven transporters is essential for lysosomal homeostasis, amino acid recycling, mTOR signaling, and maintaining lysosomal pH. To unravel the mechanisms of these transporters, we focus on cystinosin, a prototypical lysosomal amino acid transporter that exports cystine to the cytosol, where its reduction to cysteine supplies this limiting amino acid for diverse fundamental processes and controlling nutrient adaptation. Cystinosin mutations cause cystinosis, a devastating lysosomal storage disease. Here, we present structures of human cystinosin in lumen-open, cytosol-open, and cystine-bound states, which uncover the cystine recognition mechanism and capture the key conformational states of the transport cycle. Our structures, along with functional studies and double electron-electron resonance spectroscopic investigations, reveal the molecular basis for the transporter's conformational transitions and protonation switch, show conformation-dependent Ragulator-Rag complex engagement, and demonstrate an unexpected activation mechanism. These findings provide molecular insights into lysosomal amino acid efflux and a potential therapeutic strategy.
External linksCell / PubMed:36113465 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution3.0 - 3.4 Å
Structure data

27488

8dke

EMDB-27488, PDB-8dke:
Cryo-EM structure of cystinosin in a cytosol-open state
Method: EM (single particle) / Resolution: 3.18 Å

27489

8dki

EMDB-27489, PDB-8dki:
Cryo-EM structure of cystinosin in a lumen-open state
Method: EM (single particle) / Resolution: 3.32 Å

27490

8dkm

EMDB-27490, PDB-8dkm:
Cryo-EM structure of cystine-bound cystinosin in a lumen-open state
Method: EM (single particle) / Resolution: 3.39 Å

27492

8dkw

EMDB-27492, PDB-8dkw:
Cryo-EM structure of cystinosin N288K mutant in a cytosol-open state at pH5.0
Method: EM (single particle) / Resolution: 3.09 Å

27493

8dkx

EMDB-27493, PDB-8dkx:
Cryo-EM structure of cystinosin N288K mutant in a cytosol-open state at pH7.5
Method: EM (single particle) / Resolution: 3.0 Å

PDB-8dyp:
Crystal structure of human cystine transporter cystinosin
Method: X-RAY DIFFRACTION / Resolution: 3.4 Å

Chemicals

ChemComp-IYY:
L-cystine / Cystine

ChemComp-SO4:
SULFATE ION / Sulfate

ChemComp-OLC:
(2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
  • synthetic construct (others)
KeywordsMEMBRANE PROTEIN/Transport protein / Cystine / transporter / lysosome / MEMBRANE PROTEIN / MEMBRANE PROTEIN-Transport protein complex / TRANSPORT PROTEIN / Lysosomal transporter / Proton-coupled transporter / Cystine transporter / Cystinosis

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