Rational coupled dynamics network manipulation rescues disease-relevant mutant cystic fibrosis transmembrane conductance regulator

Elizabeth A. Proctor, Pradeep Kota, Andrei A. Aleksandrov, Lihua He, John R. Riordan, Nikolay V. Dokholyan

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1237-1246
Number of pages10
JournalChemical Science
Volume6
Issue number2
DOIs
StatePublished - Feb 1 2015

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Cystic Fibrosis Transmembrane Conductance Regulator
Proteins
Ion Channels
Nucleotides

All Science Journal Classification (ASJC) codes

  • Chemistry(all)

Cite this

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abstract = "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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Rational coupled dynamics network manipulation rescues disease-relevant mutant cystic fibrosis transmembrane conductance regulator. / Proctor, Elizabeth A.; Kota, Pradeep; Aleksandrov, Andrei A.; He, Lihua; Riordan, John R.; Dokholyan, Nikolay V.

In: Chemical Science, Vol. 6, No. 2, 01.02.2015, p. 1237-1246.

Research output: Contribution to journalArticle

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