2. Academic Validation
  3. CryoEM structure of the human SLC4A4 sodium-coupled acid-base transporter NBCe1

CryoEM structure of the human SLC4A4 sodium-coupled acid-base transporter NBCe1

  • Nat Commun. 2018 Mar 2;9(1):900. doi: 10.1038/s41467-018-03271-3.
Kevin W Huynh 1 2,  Jiansen Jiang 2 3,  Natalia Abuladze 1,  Kirill Tsirulnikov 1,  Liyo Kao 1,  Xuesi Shao 4,  Debra Newman 1,  Rustam Azimov 1,  Alexander Pushkin 5,  Z Hong Zhou 6 7,  Ira Kurtz 8 9
Affiliations

Affiliations

  • 1 Department of Medicine, Division of Nephrology, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
  • 2 California NanoSystems Institute, University of California, Los Angeles, CA, 90095, USA.
  • 3 Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, 90095, USA.
  • 4 Department of Neurobiology, University of California, Los Angeles, CA, 90095, USA.
  • 5 Department of Medicine, Division of Nephrology, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA. [email protected].
  • 6 California NanoSystems Institute, University of California, Los Angeles, CA, 90095, USA. [email protected].
  • 7 Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, 90095, USA. [email protected].
  • 8 Department of Medicine, Division of Nephrology, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA. [email protected].
  • 9 Brain Research Institute, University of California, Los Angeles, CA, 90095, USA. [email protected].
PMID: 29500354 DOI: 10.1038/s41467-018-03271-3
Abstract

Na+-coupled acid-base transporters play essential roles in human biology. Their dysfunction has been linked to Cancer, heart, and brain disease. High-resolution structures of mammalian Na+-coupled acid-base transporters are not available. The sodium-bicarbonate cotransporter NBCe1 functions in multiple organs and its mutations cause blindness, abnormal growth and blood chemistry, migraines, and impaired cognitive function. Here, we have determined the structure of the membrane domain dimer of human NBCe1 at 3.9 Å resolution by cryo electron microscopy. Our atomic model and functional mutagenesis revealed the ion accessibility pathway and the ion coordination site, the latter containing residues involved in human disease-causing mutations. We identified a small number of residues within the ion coordination site whose modification transformed NBCe1 into an anion exchanger. Our data suggest that symporters and exchangers utilize comparable transport machinery and that subtle differences in their substrate-binding regions have very significant effects on their transport mode.

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