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

Author

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  • Yongchan Lee

    (Max Planck Institute of Biophysics
    Yokohama City University)

  • Pattama Wiriyasermkul

    (The Jikei University School of Medicine
    Nara Medical University)

  • Pornparn Kongpracha

    (The Jikei University School of Medicine
    Nara Medical University)

  • 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
    Nara Medical University)

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.

Suggested Citation

  • Yongchan Lee & Pattama Wiriyasermkul & Pornparn Kongpracha & Satomi Moriyama & Deryck J. Mills & Werner Kühlbrandt & Shushi Nagamori, 2022. "Ca2+-mediated higher-order assembly of heterodimers in amino acid transport system b0,+ biogenesis and cystinuria," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30293-9
    DOI: 10.1038/s41467-022-30293-9
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    References listed on IDEAS

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    1. Katharina E. J. Jungnickel & Joanne L. Parker & Simon Newstead, 2018. "Structural basis for amino acid transport by the CAT family of SLC7 transporters," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    2. Renhong Yan & Xin Zhao & Jianlin Lei & Qiang Zhou, 2019. "Structure of the human LAT1–4F2hc heteromeric amino acid transporter complex," Nature, Nature, vol. 568(7750), pages 127-130, April.
    3. Harini Krishnamurthy & Chayne L. Piscitelli & Eric Gouaux, 2009. "Unlocking the molecular secrets of sodium-coupled transporters," Nature, Nature, vol. 459(7245), pages 347-355, May.
    4. Kallol Gupta & Joseph A. C. Donlan & Jonathan T. S. Hopper & Povilas Uzdavinys & Michael Landreh & Weston B. Struwe & David Drew & Andrew J. Baldwin & Phillip J. Stansfeld & Carol V. Robinson, 2017. "The role of interfacial lipids in stabilizing membrane protein oligomers," Nature, Nature, vol. 541(7637), pages 421-424, January.
    5. Joanne L. Parker & Justin C. Deme & Dimitrios Kolokouris & Gabriel Kuteyi & Philip C. Biggin & Susan M. Lea & Simon Newstead, 2021. "Molecular basis for redox control by the human cystine/glutamate antiporter system xc−," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    6. Ekaitz Errasti-Murugarren & Joana Fort & Paola Bartoccioni & Lucía Díaz & Els Pardon & Xavier Carpena & Meritxell Espino-Guarch & Antonio Zorzano & Christine Ziegler & Jan Steyaert & Juan Fernández-Re, 2019. "L amino acid transporter structure and molecular bases for the asymmetry of substrate interaction," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
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    2. Di Wu & Renhong Yan & Siyuan Song & Andrew K. Swansiger & Yaning Li & James S. Prell & Qiang Zhou & Carol V. Robinson, 2024. "The complete assembly of human LAT1-4F2hc complex provides insights into its regulation, function and localisation," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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