Structural changes of CFTR R region upon phosphorylation: a plastic platform for intramolecular and intermolecular interactions

Authors

  • Zoltan Bozoky,

    1. Program in Molecular Structure and Function, Hospital for Sick Children, Toronto, Ontario, Canada
    2. Department of Biochemistry, University of Toronto, Ontario, Canada
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  • Mickael Krzeminski,

    1. Program in Molecular Structure and Function, Hospital for Sick Children, Toronto, Ontario, Canada
    2. Department of Biochemistry, University of Toronto, Ontario, Canada
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  • P. Andrew Chong,

    1. Program in Molecular Structure and Function, Hospital for Sick Children, Toronto, Ontario, Canada
    2. Department of Biochemistry, University of Toronto, Ontario, Canada
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  • Julie D. Forman-Kay

    Corresponding author
    1. Program in Molecular Structure and Function, Hospital for Sick Children, Toronto, Ontario, Canada
    2. Department of Biochemistry, University of Toronto, Ontario, Canada
    • Correspondence

      J. D. Forman-Kay, Molecular Structure and Function Program, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G1X8

      Fax: +1 416 813 5022

      Tel: +1 416 813 5358

      E-mail: forman@sickkids.ca

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Abstract

Chloride channel gating and trafficking of the cystic fibrosis transmembrane conductance regulator (CFTR) are regulated by phosphorylation. Intrinsically disordered segments of the protein are responsible for phospho-regulation, particularly the regulatory (R) region that is a target for several kinases and phosphatases. The R region remains disordered following phosphorylation, with different phosphorylation states sampling various conformations. Recent studies have demonstrated the crucial role that intramolecular and intermolecular interactions of the R region play in CFTR regulation. Different partners compete for the same binding segment, with the R region containing multiple overlapping binding elements. The non-phosphorylated R region interacts with the nucleotide binding domains and inhibits channel activity by blocking heterodimerization. Phosphorylation shifts the equilibrium such that the R region is excluded from the dimer interface, facilitating gating and processing by stimulating R region interactions with other domains and proteins. The dynamic conformational sampling and transient binding of the R region to multiple partners enables complex control of CFTR channel activity and trafficking.

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