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 & Yan Zhao
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.
附件下载：
Structure and mechanism of the human NHE1-CHP1 complex, Nat Commun, 9 Jun 2021
Nature Communications, 9 June, 2021, DOI：https://doi.org/10.1038/s41467-021-23496-z
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 & Yan Zhao
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.
文章链接：https://www.nature.com/articles/s41467-021-23496-z
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