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

Nat Commun. 2022 May 16;13(1):2708. doi: 10.1038/s41467-022-30293-9.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport Systems / metabolism
  • Amino Acid Transport Systems, Basic* / metabolism
  • Amino Acid Transport Systems, Basic* / ultrastructure
  • Calcium* / chemistry
  • Calcium* / metabolism
  • Cystine / metabolism
  • Cystinuria* / genetics
  • Cystinuria* / metabolism
  • Humans


  • Amino Acid Transport Systems
  • Amino Acid Transport Systems, Basic
  • Cystine
  • Calcium

Supplementary concepts

  • Cystinuria type 1