title: Architecture of the cystic fibrosis transmembrane conductance regulator protein and structural changes associated with phosphorylation and nucleotide binding.
abstract: We describe biochemical and structural studies of the isolated cystic fibrosis transmembrane conductance regulator (CFTR) protein. Using electron cryomicroscopy, low resolution three-dimensional structures have been obtained for the non-phosphorylated protein in the absence of nucleotide and for the phosphorylated protein with ATP. In the latter state, the cytosolic nucleotide-binding domains move closer together, forming a more compact packing arrangement. Associated with this is a reorganization within the cylindrical transmembrane domains, consistent with a shift from an inward-facing to outward-facing configuration. A region of density in the non-phosphorylated protein that extends from the bottom of the cytosolic regions up to the transmembrane domains is hypothesised to represent the unique regulatory region of CFTR. These data offer insights into the architecture of this ATP-binding cassette protein, and shed light on the global motions associated with nucleotide binding and priming of the chloride channel via phosphorylation of the regulatory region.
authors.affiliation: Faculty of Life Sciences, The University of Manchester, MIB, Manchester M1 7DN, UK.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.forename: Luba A
authors.initials: LA
authors.lastname: Aleksandrov
authors.forename: Zhefeng
authors.initials: Z
authors.lastname: Zhao
authors.forename: James R
authors.initials: JR
authors.lastname: Birtley
authors.forename: John R
authors.initials: JR
authors.lastname: Riordan
authors.forename: Robert C
authors.initials: RC
authors.lastname: Ford
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry* / Q000378:metabolism; D020285:Cryoelectron Microscopy; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation; D011487:Protein Conformation; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000255:Adenosine Triphosphate