TY - JOUR
T1 - Structure and mechanism of human cystine exporter cystinosin
AU - Guo, Xue
AU - Schmiege, Philip
AU - Assafa, Tufa E.
AU - Wang, Rong
AU - Xu, Yan
AU - Donnelly, Linda
AU - Fine, Michael
AU - Ni, Xiaodan
AU - Jiang, Jiansen
AU - Millhauser, Glenn
AU - Feng, Liang
AU - Li, Xiaochun
N1 - Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2022/9/29
Y1 - 2022/9/29
N2 - 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.
AB - 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.
KW - DEER
KW - Keywords
KW - Ragulator-Rag complex
KW - X-ray crystallography
KW - cryo-EM
KW - cystinosin
KW - cystinosis
KW - fast adaptation
KW - lysosomal storage disease
KW - lysosomal transporter
KW - membrane protein dynamics
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UR - http://www.scopus.com/inward/citedby.url?scp=85138761289&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2022.08.020
DO - 10.1016/j.cell.2022.08.020
M3 - Article
C2 - 36113465
AN - SCOPUS:85138761289
SN - 0092-8674
VL - 185
SP - 3739-3752.e18
JO - Cell
JF - Cell
IS - 20
ER -