title: Rational Coupled Dynamics Network Manipulation Rescues Disease-Relevant Mutant Cystic Fibrosis Transmembrane Conductance Regulator.
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.
authors: Curriculum in Bioinformatics and Computational Biology, University of North Carolina, Chapel Hill, NC 27599, USA ; Program in Molecular and Cellular Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: Elizabeth A
authors: EA
authors: Proctor
authors: Program in Molecular and Cellular Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA ; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: Pradeep
authors: P
authors: Kota
authors: Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA ; Cystic Fibrosis Treatment and Research Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: Andrei A
authors: AA
authors: Aleksandrov
authors: Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA ; Cystic Fibrosis Treatment and Research Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: Lihua
authors: L
authors: He
authors: Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA ; Cystic Fibrosis Treatment and Research Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: John R
authors: JR
authors: Riordan
authors: Curriculum in Bioinformatics and Computational Biology, University of North Carolina, Chapel Hill, NC 27599, USA ; Program in Molecular and Cellular Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA ; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA ; Cystic Fibrosis Treatment and Research Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: Nikolay V
authors: NV
authors: Dokholyan