title: Structural changes of CFTR R region upon phosphorylation: a plastic platform for intramolecular and intermolecular interactions.
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.
authors.affiliation: Program in Molecular Structure and Function, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Bozoky
authors.forename: Mickael
authors.initials: M
authors.lastname: Krzeminski
authors.forename: P Andrew
authors.initials: PA
authors.lastname: Chong
authors.forename: Julie D
authors.initials: JD
authors.lastname: Forman-Kay
mesh_terms: D001665:Binding Sites; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D010766:Phosphorylation; D011485:Protein Binding; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D015398:Signal Transduction
chemical_list: C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: IDP; binding; disordered; hub; post-translational modification; regulation