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

Yishuo Lu, Peng Zuo, Hongyi Chen, Hui Shan, Weize Wang, Zonglin Dai, He Xu, Yayu Chen, Ling Liang, Dian Ding, Yan Jin and Yuxin Yin ()
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Yishuo Lu: Peking University Shenzhen Hospital
Peng Zuo: Peking University Health Science Center
Hongyi Chen: Peking University Shenzhen Hospital
Hui Shan: Peking University Shenzhen Hospital
Weize Wang: Peking University
Zonglin Dai: Peking University Health Science Center
He Xu: XtalPi
Yayu Chen: XtalPi
Ling Liang: Peking University Health Science Center
Dian Ding: Peking University Shenzhen Hospital
Yan Jin: Peking University Health Science Center
Yuxin Yin: Peking University Shenzhen Hospital

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41924-0

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