# The CFTR Interactome

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2022 · $539,068

## Abstract

Project Summary
Cystic Fibrosis (CF) is caused by mutation of the CFTR gene and is one of the most common inherited
childhood diseases, impacting 1 in 4,000 children born in the US (www.cff.org). Today, CF disease symptoms
in patients with the most common mutation (∆F508 CFTR) can be improved with three different drug
combinations. However, the drugs have negative side effects that reduce patient compliance to therapeutic
regimens and pose long-term health risks. Additionally, many other common CF-causing mutations respond
poorly or not at all to any of the current CF drugs, leaving CF patients carrying these mutations only with
symptomatic therapy. Efforts to develop new compounds for such CF variants are hampered by the lack of
protein structures that would reveal the conformational defects of these variants, mostly due to technical
difficulties in expressing and purifying sufficient quantities of these unstable proteins. To characterize the
conformational defects of misfolded CFTR variants and to aid in the development of new therapies, we
previously developed Covalent Protein Painting (CPP), a novel method for in vivo structural characterization of
proteins by mass spectrometry. Here, we propose to develop a more sensitive and multiplexable CPP method,
named bioTMT-CPP, that will facilitate detection and comparison of CFTR conformational changes between
samples. The new method will facilitate the characterization of conformational defects in misfolded CFTR
variants that are refractory to current therapies. Furthermore, our approach has the potential to pinpoint drug
binding sites and identify the mechanism of action of current CF drugs, which remain unknown for three of the
four active compounds. Such knowledge will help to rationalize drug combination therapies. We also propose
to functionally characterize a novel CFTR conformation that we discovered by CPP and that is attained by
misfolded and inactive CFTR, likely during protein trafficking. Insight into the molecular mechanisms that
stabilize this conformation as well as those that release it into an active conformation will be invaluable for
further corrector drug development and will benefit all CF patients.

## Key facts

- **NIH application ID:** 10504288
- **Project number:** 1R01HL165168-01
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** John R Yates III
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $539,068
- **Award type:** 1
- **Project period:** 2022-08-05 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10504288

## Citation

> US National Institutes of Health, RePORTER application 10504288, The CFTR Interactome (1R01HL165168-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10504288. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*