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-Structure paper
タイトル | Ca-mediated higher-order assembly of heterodimers in amino acid transport system b biogenesis and cystinuria. |
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ジャーナル・号・ページ | Nat Commun, Vol. 13, Issue 1, Page 2708, Year 2022 |
掲載日 | 2022年5月16日 |
著者 | Yongchan Lee / Pattama Wiriyasermkul / Pornparn Kongpracha / Satomi Moriyama / Deryck J Mills / Werner Kühlbrandt / Shushi Nagamori / |
PubMed 要旨 | 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 ...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. |
リンク | Nat Commun / PubMed:35577790 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.68 - 3.05 Å |
構造データ | EMDB-12296, PDB-7nf6: EMDB-12297: Ovine rBAT ectodomain homodimer, C2-symmetry EMDB-12298: Ovine (b0,+AT-rBAT)2 hetero-tetramer, consensus refinement, C2-symmetry |
化合物 | ChemComp-CLR: ChemComp-LBN: ChemComp-CA: ChemComp-NAG: |
由来 |
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キーワード | TRANSLOCASE / Transporter / Cystinuria / Complex / Ectodomain |