# The Biology of NBCe1 in Health and Disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $627,950

## Abstract

PROJECT SUMMARY
SLC4 proteins in the kidney play an essential role in mediating the coupled transport (symporters,
exchangers) of Na+, HCO3⎯, CO32⎯, and Cl⎯ in the proximal tubule and collecting duct. Infants and children
with mutations in the electrogenic Na+-CO32⎯ symporter NBCe1 and the Cl⎯/HCO3⎯ exchanger AE1 develop
severe proximal and distal renal tubular acidosis respectively. How disease causing mutations impair their
transport mechanisms at the molecular level is unknown. Towards this goal, we have recently solved by
cryoelectron microscopy (cryoEM) the outward facing structure of NBCe1, the inward and outward facing
structures of AE1, and have obtained 2D class averages of the Na+-CO32⎯/Cl⎯ exchanger NDCBE
representing major advances in the field. These significant advances coupled with our preliminary functional
mutagenesis and Molecular Dynamics computational analyses make it possible for the first time in the
transport field to achieve the long-term objective of understanding the detailed structure-functional
properties of SLC4 transporters and their impairment by disease causing mutations. To accomplish this
objective, the project addresses the following specific aims: Aim 1: Structural Determinants of the AE1,
NBCe1, and NDCBE Ion Coordination Sites, Transport Modes and Ion Specificities: In this aim, using
cryoEM, functional mutagenesis and Molecular Dynamics computational analyses, the hypothesis that the
ion coordination sites in these transporters encode both their respective transport modes and unique ion
transport specificities will be examined. Aim 2: Characterize the Structural Components of AE1, NBCe1 and
NDCBE Permeation Pores, Ion Selectivity and Energetics: In this aim, using cryoEM, functional mutagenesis
and Molecular Dynamics computational analyses, the hypothesis that differences in the structure and
energetics of ion permeation among these transporters plays an important role in determining the selectivity
of ions reaching their coordination sites in both outward and inward facing conformations will be examined.
Aim 3: Transport Models for AE1, NBCe1 and NDCBE, and Characterization of the Transport Abnormalities
Induced by Renal Tubular Acidosis Causing Mutations: The dynamic transport models of AE1, NBCe1 and
NDCBE will be generated based on preliminary data, and the results obtained in Aims 1 and 2. How disease
causing mutations impair these mechanistic transporter molecular models will be determined. This proposal
represents a significant contribution to Nephrology and Medicine given the importance of SLC4 transporters
in regulating kidney ion balance, systemic acid-base chemistry, blood pressure, and the maintenance of cell
function and growth.

## Key facts

- **NIH application ID:** 10126829
- **Project number:** 5R01DK077162-12
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** IRA KURTZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $627,950
- **Award type:** 5
- **Project period:** 2019-03-19 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10126829

## Citation

> US National Institutes of Health, RePORTER application 10126829, The Biology of NBCe1 in Health and Disease (5R01DK077162-12). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10126829. Licensed CC0.

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