# Molecular Mechanism of TMEM16A Surface Stabilization by CLCA1

> **NIH NIH F30** · WASHINGTON UNIVERSITY · 2020 · $49,738

## Abstract

Project Summary
 Cystic fibrosis (CF) is a genetically inherited disease that is due to loss-of-function mutations in the
CFTR gene. Thousands of mutations in CFTR have been identified and much of the efforts for CF therapy
have focused on rescuing the dysfunction of the CFTR mutations. However, developing therapies for the
thousands of mutations that are thought to cause to CF would be challenging. Others have therefore sought to
activate alternative sources of anion channels in the lungs, with the expectation that these therapies would not
depend on the specific CFTR mutation. In the past decade, the identification of one such candidate, the
calcium-activated chloride channel, TMEM16A, has prompted some groups to propose activation of this
channel to restore anion currents in CF airway.
 Our group has found that CLCA1, a specific and direct regulator of TMEM16A, can increase chloride
current density by preventing removal of the channel from the plasma membrane. The 18 kDa vWA domain
within CLCA1 is able to carry out this activity alone, in HEK293T cells and in primary CF airway cells. These
findings raise the question of how a fully secreted regulator is able to influence the intracellular trafficking of a
channel. Furthermore, it not known whether the vWA domain of CLCA1 can restore mucous properties in CF
airway epithelium. To address these questions, I will study the cellular mechanism by which the CLCA1 vWA
domain affects trafficking of TMEM16A using imaging methods and mass spectrometry. Using X-ray
crystallography, NMR and biophysical binding studies, I will identify the key molecular contacts that govern the
interaction of these proteins. Finally, I will apply the vWA domain to differentiated airway culture derived from
primary CF airway cells to study its effects on TMEM16A trafficking, epithelial anion secretion and epithelial
mucous properties. The ultimate goal of this project is to understand the mechanism of the CLCA1-TMEM16A
interaction as a model for developing universal therapy for cystic fibrosis.

## Key facts

- **NIH application ID:** 9934263
- **Project number:** 5F30HL140783-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Kayla Nicole Berry
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $49,738
- **Award type:** 5
- **Project period:** 2018-06-01 → 2021-05-21

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934263

## Citation

> US National Institutes of Health, RePORTER application 9934263, Molecular Mechanism of TMEM16A Surface Stabilization by CLCA1 (5F30HL140783-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9934263. Licensed CC0.

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