Structural basis of autoinhibition of the human NHE3-CHP1 complex

Author:

Dong Yanli12ORCID,Li Hang12ORCID,Ilie Alina3ORCID,Gao Yiwei12ORCID,Boucher Annie3ORCID,Zhang Xuejun Cai1ORCID,Orlowski John3ORCID,Zhao Yan1ORCID

Affiliation:

1. National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.

2. College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.

3. Department of Physiology, McGill University, Montreal, Canada.

Abstract

Sodium-proton exchanger 3 (NHE3/SLC9A3) located in the apical membrane of renal and gastrointestinal epithelia mediates salt and fluid absorption and regulates pH homeostasis. As an auxiliary regulatory factor of NHE proteins, calcineurin B homologous protein 1 (CHP1) facilitates NHE3 maturation, plasmalemmal expression, and pH sensitivity. Dysfunctions of NHE3 are associated with renal and digestive system disorders. Here, we report the cryo–electron microscopy structure of the human NHE3-CHP1 complex in its inward-facing conformation. We found that a cytosolic helix-loop-helix motif in NHE3 blocks the intracellular cavity formed between the core and dimerization domains, functioning as an autoinhibitory element and hindering substrate transport. Furthermore, two phosphatidylinositol molecules are found to bind to the peripheric juxtamembrane sides of the complex, function as anchors to stabilize the complex, and may thus enhance its transport activity.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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