Rational coupled dynamics network manipulation rescues disease-relevant mutant cystic fibrosis transmembrane conductance regulator
Open accessAbstract
Many cellular functions necessary for life are tightly regulated by protein allosteric conformational change, and correlated dynamics between protein regions has been found to contribute to the function of proteins not previously considered allosteric. The ability to map and control such dynamic coupling would thus create opportunities for the extension of current therapeutic design strategy. Here, we present an approach to determine the networks of residues involved in the transfer of correlated motion across a protein, and apply our approach to rescue disease-causative mutant cystic fibrosis transmembrane regulator (CFTR) ion channels, ΔF508 and ΔI507, which together constitute over 90% of cystic fibrosis cases. We show that these mutations perturb dynamic coupling within the first nucleotide-binding domain (NBD1), and uncover a critical residue that mediates trans-domain coupled dynamics. By rationally designing a mutation to this residue, we improve aberrant dynamics of mutant CFTR as well as enhance surface expression and function of both mutants, demonstrating the rescue of a disease mutation by rational correction of aberrant protein dynamics.
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Computational procedures can identify solvent-accessible allosteric sites on a target protein.
“The approach consists of using computational procedures to identify solvent-accessible allosteric sites (Proctor et al., 2015) on a target protein and physically engineering naturally occurring light-sensitive or ligand-sensitive domains into these sites.”
From Allostery in Its Many Disguises: From Theory to Applications (2019) · cites this paper as Proctor et al., 2015
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Self-citation
- Authors
- Proctor, E. A., Kota, P., Aleksandrov, A. A., He, L., Riordan, J. R., & Dokholyan, N. V.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Dokholyan, Nikolay V.
- Venue
- Chemical Science
- Publisher
- Royal Society of Chemistry (RSC)
- Published
- 2015
- Volume
- 6
- Issue
- 2
- Pages
- 1237-1246
- ISSN
- 2041-6520 (ISSN-L)
- 2041-6539
- PMC
- PMC4324596
- OpenAlex
- W1994987010
- Cited by
- 61
- References
- 51
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2023: 9 · 2022: 3 · 2021: 6 · 2020: 9 · 2019: 10 · 2018: 5 · 2017: 4 · 2016: 6 · 2015: 4
- FWCI
- 3.74
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Chemical Science (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (DK051619)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- cystic fibrosis transmembrane conductance regulator, CFTR, F508del mutation, cystic fibrosis, protein dynamics, correlated motions, allosteric communication, NBD1, cell surface expression
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