title: Structural models of CFTR-AMPK and CFTR-PKA interactions: R-domain flexibility is a key factor in CFTR regulation.
abstract: Cystic fibrosis (CF), the most common lethal genetic disease among Caucasians, is caused by mutations in cystic fibrosis transmembrane conductance regulator (CFTR). CFTR's main role is to transport chloride ions across epithelial cell membranes. It also regulates many cell functions. However, the exact role of CFTR in cellular processes is not yet fully understood. It is recognized that a key factor in CFTR-related regulation is its phosphorylation state. The important kinases regulating CFTR are cAMP-dependent protein kinase A (PKA) and 5'-AMP-activated protein kinase (AMPK). PKA and AMPK have opposite effects on CFTR activity despite their highly similar structures and recognition motifs. Utilizing homology modeling, in silico mutagenesis and literature mining, we supplement available information regarding the atomic-resolution structures of PKA, AMPK and CFTR, and the complexes CFTR-PKA and CFTR-AMPK. The atomic-resolution structural predictions reveal an unexpected availability of CFTR Ser813 for phosphorylation by both PKA and AMPK. These results indicate the key role of the structural flexibility of the serine-rich R-domain in CFTR regulation by phosphorylation.
authors: Department of Bioinformatics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
authors: Marian
authors: M
authors: Siwiak
authors: Aleksander
authors: A
authors: Edelman
authors: Piotr
authors: P
authors: Zielenkiewicz
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000595:Amino Acid Sequence; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D010766:Phosphorylation; D054730:Protein Interaction Domains and Motifs; D017434:Protein Structure, Tertiary; D020539:Sequence Analysis, Protein
chemical_list: C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D017868:Cyclic AMP-Dependent Protein Kinases; D055372:AMP-Activated Protein Kinases