Structural basis for proton coupled cystine transport by cystinosin

Amino acid transporters play a key role controlling the flow of nutrients across the lysosomal membrane and regulating metabolism in the cell. Mutations in the gene encoding the transporter cystinosin result in cystinosis, an autosomal recessive metabolic disorder characterised by the accumulation o...

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Bibliographic Details
Published in:Nature communications 2022-08, Vol.13 (1), p.1-12, Article 4845
Main Authors: Löbel, Mark, Salphati, Sacha P., El Omari, Kamel, Wagner, Armin, Tucker, Stephen J., Parker, Joanne L., Newstead, Simon
Format: Article
Language:English
Subjects:
631/45/535
631/535/1266
Amino acids
Arabidopsis thaliana
Coupling (molecular)
Crystal structure
Crystals
Cystine
Cystinosis
Cytoplasm
Hereditary diseases
Humanities and Social Sciences
Metabolic disorders
multidisciplinary
Mutation
Nutrients
Protons
Recognition
Science
Science (multidisciplinary)
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Summary:Amino acid transporters play a key role controlling the flow of nutrients across the lysosomal membrane and regulating metabolism in the cell. Mutations in the gene encoding the transporter cystinosin result in cystinosis, an autosomal recessive metabolic disorder characterised by the accumulation of cystine crystals in the lysosome. Cystinosin is a member of the PQ-loop family of solute carrier (SLC) transporters and uses the proton gradient to drive cystine export into the cytoplasm. However, the molecular basis for cystinosin function remains elusive, hampering efforts to develop novel treatments for cystinosis and understand the mechanisms of ion driven transport in the PQ-loop family. To address these questions, we present the crystal structures of cystinosin from Arabidopsis thaliana in both apo and cystine bound states. Using a combination of in vitro and in vivo based assays, we establish a mechanism for cystine recognition and proton coupled transport. Mutational mapping and functional characterisation of human cystinosin further provide a framework for understanding the molecular impact of disease-causing mutations. Mutations in CTNS, the lysosomal cystine-proton symporter, cause cystinosis. Here authors report crystal structures of CTNS from Arabidopsis thaliana in complex with cystine, and establish the mode of ligand recognition and mechanism for proton-coupled cystine export from the lysosome.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-022-32589-2