7NF8

Ovine (b0,+AT-rBAT)2 hetero-tetramer, asymmetric unit, rigid-body fitted

Summary for 7NF8

• Entry DOI: 10.2210/pdb7nf8/pdb
• EMDB information: 12298
• Descriptor: B(0,+)-type amino acid transporter 1, neutral and basic amino acid transport protein rBAT, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• Functional Keywords: transporter, cystinuria, complex, translocase
• Biological source: Ovis aries (Sheep); More
• Total number of polymer chains: 2
• Total formula weight: 138379.42

Authors

Lee, Y.,Kuehlbrandt, W. (deposition date: 2021-02-05, release date: 2022-01-19, Last modification date: 2024-10-16)

Primary citation

Lee, Y.,Wiriyasermkul, P.,Kongpracha, P.,Moriyama, S.,Mills, D.J.,Kuhlbrandt, W.,Nagamori, S.
Ca 2+ -mediated higher-order assembly of heterodimers in amino acid transport system b 0,+ biogenesis and cystinuria.
Nat Commun, 13:2708-2708, 2022

PubMed 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 bAT, which constitute system b, 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 Ca mediates higher-order assembly of system b. Ca stabilizes the interface between two rBAT molecules, leading to super-dimerization of bAT-rBAT, which in turn facilitates N-glycan maturation and protein trafficking. A cystinuria mutant T216M and mutations of the Ca 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 b 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.

PubMed: 35577790
DOI: 10.1038/s41467-022-30293-9

Experimental method

ELECTRON MICROSCOPY (2.83 Å)