Ca2+-mediated higher-order assembly of heterodimers in amino acid transport system b0,+ biogenesis and cystinuria

Yongchan Lee (), Pattama Wiriyasermkul, Pornparn Kongpracha, Satomi Moriyama, Deryck J. Mills, Werner Kühlbrandt and Shushi Nagamori ()
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Yongchan Lee: Max Planck Institute of Biophysics
Pattama Wiriyasermkul: The Jikei University School of Medicine
Pornparn Kongpracha: The Jikei University School of Medicine
Satomi Moriyama: Nara Medical University
Deryck J. Mills: Max Planck Institute of Biophysics
Werner Kühlbrandt: Max Planck Institute of Biophysics
Shushi Nagamori: The Jikei University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract Cystinuria is a genetic disorder characterized by overexcretion of dibasic amino acids and cystine, causing recurrent kidney stones and kidney failure. Mutations of the regulatory glycoprotein rBAT and the amino acid transporter b0,+AT, which constitute system b0,+, are linked to type I and non-type I cystinuria respectively and they exhibit distinct phenotypes due to protein trafficking defects or catalytic inactivation. Here, using electron cryo-microscopy and biochemistry, we discover that Ca2+ mediates higher-order assembly of system b0,+. Ca2+ stabilizes the interface between two rBAT molecules, leading to super-dimerization of b0,+AT–rBAT, which in turn facilitates N-glycan maturation and protein trafficking. A cystinuria mutant T216M and mutations of the Ca2+ site of rBAT cause the loss of higher-order assemblies, resulting in protein trapping at the ER and the loss of function. These results provide the molecular basis of system b0,+ biogenesis and type I cystinuria and serve as a guide to develop new therapeutic strategies against it. More broadly, our findings reveal an unprecedented link between transporter oligomeric assembly and protein-trafficking diseases.

Date: 2022
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DOI: 10.1038/s41467-022-30293-9

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