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Structural insights into the conformational changes of BTR1/SLC4A11 in complex with PIP2

Author

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  • Yishuo Lu

    (Peking University Shenzhen Hospital
    Peking University)

  • Peng Zuo

    (Peking University Health Science Center)

  • Hongyi Chen

    (Peking University Shenzhen Hospital
    Peking University)

  • Hui Shan

    (Peking University Shenzhen Hospital)

  • Weize Wang

    (Peking University
    Peking University Health Science Center)

  • Zonglin Dai

    (Peking University Health Science Center)

  • He Xu

    (XtalPi)

  • Yayu Chen

    (XtalPi)

  • Ling Liang

    (Peking University Health Science Center
    Peking University Health Science Center)

  • Dian Ding

    (Peking University Shenzhen Hospital
    Peking University Health Science Center)

  • Yan Jin

    (Peking University Health Science Center)

  • Yuxin Yin

    (Peking University Shenzhen Hospital
    Peking University
    Peking University Health Science Center)

Abstract

BTR1 (SLC4A11) is a NH3 stimulated H+ (OH-) transporter belonging to the SLC4 family. Dysfunction of BTR1 leads to diseases such as congenital hereditary endothelial dystrophy (CHED) and Fuchs endothelial corneal dystrophy (FECD). However, the mechanistic basis of BTR1 activation by alkaline pH, transport activity regulation and pathogenic mutations remains elusive. Here, we present cryo-EM structures of human BTR1 in the outward-facing state in complex with its activating ligands PIP2 and the inward-facing state with the pathogenic R125H mutation. We reveal that PIP2 binds at the interface between the transmembrane domain and the N-terminal cytosolic domain of BTR1. Disruption of either the PIP2 binding site or protonation of PIP2 phosphate groups by acidic pH can transform BTR1 into an inward-facing conformation. Our results provide insights into the mechanisms of how the transport activity and conformation changes of BTR1 are regulated by PIP2 binding and interaction of TMD and NTD.

Suggested Citation

  • Yishuo Lu & Peng Zuo & Hongyi Chen & Hui Shan & Weize Wang & Zonglin Dai & He Xu & Yayu Chen & Ling Liang & Dian Ding & Yan Jin & Yuxin Yin, 2023. "Structural insights into the conformational changes of BTR1/SLC4A11 in complex with PIP2," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41924-0
    DOI: 10.1038/s41467-023-41924-0
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    2. Weiqi Zhang & Dian Ding & Yishuo Lu & Hongyi Chen & Peijun Jiang & Peng Zuo & Guangxi Wang & Juan Luo & Yue Yin & Jianyuan Luo & Yuxin Yin, 2024. "Structural and functional insights into the lipid regulation of human anion exchanger 2," Nature Communications, Nature, vol. 15(1), pages 1-10, December.

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