National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)
DK077162
米国
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)
DK007789
米国
Allan Smidt Charitable Fund
米国
Factor Family Foundation
米国
Ralph Block Family Foundation
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM071940
米国
National Institutes of Health/National Institute of Dental and Craniofacial Research (NIH/NIDCR)
DE025567
米国
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
AI094386
米国
National Institutes of Health/National Center for Research Resources (NIH/NCRR)
1S10RR23057
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
1U24GM116792
米国
National Science Foundation (NSF, United States)
DBI-1338135
米国
引用
ジャーナル: Nat Commun / 年: 2018 タイトル: CryoEM structure of the human SLC4A4 sodium-coupled acid-base transporter NBCe1. 著者: Kevin W Huynh / Jiansen Jiang / Natalia Abuladze / Kirill Tsirulnikov / Liyo Kao / Xuesi Shao / Debra Newman / Rustam Azimov / Alexander Pushkin / Z Hong Zhou / Ira Kurtz / 要旨: 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- ...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.