Structure and mechanism of the human NHE1-CHP1 complex

Yanli Dong, Yiwei Gao, Alina Ilie, DuSik Kim, Annie Boucher, Bin Li, Xuejun C. Zhang (), John Orlowski () and Yan Zhao ()
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Yanli Dong: Chinese Academy of Sciences
Yiwei Gao: Chinese Academy of Sciences
Alina Ilie: McGill University
DuSik Kim: McGill University
Annie Boucher: McGill University
Bin Li: Chinese Academy of Sciences
Xuejun C. Zhang: Chinese Academy of Sciences
John Orlowski: McGill University
Yan Zhao: Chinese Academy of Sciences

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract Sodium/proton exchanger 1 (NHE1) is an electroneutral secondary active transporter present on the plasma membrane of most mammalian cells and plays critical roles in regulating intracellular pH and volume homeostasis. Calcineurin B-homologous protein 1 (CHP1) is an obligate binding partner that promotes NHE1 biosynthetic maturation, cell surface expression and pH-sensitivity. Dysfunctions of either protein are associated with neurological disorders. Here, we elucidate structures of the human NHE1-CHP1 complex in both inward- and inhibitor (cariporide)-bound outward-facing conformations. We find that NHE1 assembles as a symmetrical homodimer, with each subunit undergoing an elevator-like conformational change during cation exchange. The cryo-EM map reveals the binding site for the NHE1 inhibitor cariporide, illustrating how inhibitors block transport activity. The CHP1 molecule differentially associates with these two conformational states of each NHE1 monomer, and this association difference probably underlies the regulation of NHE1 pH-sensitivity by CHP1.

Date: 2021
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DOI: 10.1038/s41467-021-23496-z

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