A stabilizing influence: CAL PDZ inhibition extends the half-life of ΔF508-CFTR.

From synthesis to degradation, membrane proteins navigate interwoven networks that control their localization and activity within the cell. At branchpoints within these networks, protein-protein interactions often determine the flux of individual proteins through specific pathways and thus offer targets for therapeutic modulation. The PDZ (PSD-95, Dlg, and ZO-1) proteins constitute a major family of trafficking regulators. Characterized by the presence of eponymous protein-protein interaction domains (PPIDs), PDZ proteins generally bind the C-termini of their partners and help choreograph their movements throughout the cell. The targets of PDZ regulation include the cystic fibrosis transmembrane conductance regulator (CFTR), the chloride channel mutated in patients with cystic fibrosis (CF)[1].

[1]  S. Matalon,et al.  Functional stability of rescued delta F508 cystic fibrosis transmembrane conductance regulator in airway epithelial cells. , 2010, American journal of respiratory cell and molecular biology.

[2]  J. Riordan,et al.  Modulation of endocytic trafficking and apical stability of CFTR in primary human airway epithelial cultures. , 2010, American journal of physiology. Lung cellular and molecular physiology.

[3]  M. Donowitz,et al.  Differential roles of NHERF1, NHERF2, and PDZK1 in regulating CFTR-mediated intestinal anion secretion in mice. , 2009, The Journal of clinical investigation.

[4]  Chris Sander,et al.  A Specificity Map for the PDZ Domain Family , 2008, PLoS biology.

[5]  Patrick R. Cushing,et al.  The relative binding affinities of PDZ partners for CFTR: a biochemical basis for efficient endocytic recycling. , 2008, Biochemistry.

[6]  Prisca Boisguerin,et al.  Characterization of a Putative Phosphorylation Switch: Adaptation of SPOT Synthesis to Analyze PDZ Domain Regulation Mechanisms , 2007, Chembiochem : a European journal of chemical biology.

[7]  Aleksandr Kivenson,et al.  Targeting CAL as a negative regulator of DeltaF508-CFTR cell-surface expression: an RNA interference and structure-based mutagenetic approach. , 2007, The Journal of biological chemistry.

[8]  R. Boucher.  Airway surface dehydration in cystic fibrosis: pathogenesis and therapy. , 2007, Annual review of medicine.

[9]  D. Ejima,et al.  Small molecule pharmacological chaperones: From thermodynamic stabilization to pharmaceutical drugs. , 2006, Biochimica et biophysica acta.

[10]  James Rader,et al.  Rescue of DeltaF508-CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small molecules. , 2006, American journal of physiology. Lung cellular and molecular physiology.

[11]  W. Guggino,et al.  New insights into cystic fibrosis: molecular switches that regulate CFTR , 2006 .

[12]  J. Clancy,et al.  Adenosine regulation of cystic fibrosis transmembrane conductance regulator through prostenoids in airway epithelia. , 2006, American journal of respiratory cell and molecular biology.

[13]  M. Conese,et al.  Na+/H+ Exchanger Regulatory Factor Isoform 1 Overexpression Modulates Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Expression and Activity in Human Airway 16HBE14o- Cells and Rescues ΔF508 CFTR Functional Expression in Cystic Fibrosis Cells* , 2005, Journal of Biological Chemistry.

[14]  Andrea Piserchio,et al.  Association of the cystic fibrosis transmembrane regulator with CAL: structural features and molecular dynamics. , 2005, Biochemistry.

[15]  T. Flotte,et al.  The Short Apical Membrane Half-life of Rescued ΔF508-Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Results from Accelerated Endocytosis of ΔF508-CFTR in Polarized Human Airway Epithelial Cells* , 2005, Journal of Biological Chemistry.

[16]  Kai Du,et al.  Small-molecule correctors of defective DeltaF508-CFTR cellular processing identified by high-throughput screening. , 2005, The Journal of clinical investigation.

[17]  E. Kerem.  Pharmacologic therapy for stop mutations: how much CFTR activity is enough? , 2004, Current opinion in pulmonary medicine.

[18]  Prisca Boisguerin,et al.  An improved method for the synthesis of cellulose membrane-bound peptides with free C termini is useful for PDZ domain binding studies. , 2004, Chemistry & biology.

[19]  A. Taddei,et al.  Altered channel gating mechanism for CFTR inhibition by a high‐affinity thiazolidinone blocker , 2004, FEBS letters.

[20]  Hong Yang,et al.  Thiazolidinone CFTR inhibitor identified by high-throughput screening blocks cholera toxin-induced intestinal fluid secretion. , 2002, The Journal of clinical investigation.

[21]  G. Cutting,et al.  PDZ Domain Interaction Controls the Endocytic Recycling of the Cystic Fibrosis Transmembrane Conductance Regulator* , 2002, The Journal of Biological Chemistry.

[22]  T. Noda,et al.  Lack of acrosome formation in mice lacking a Golgi protein, GOPC , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[23]  G. Novelli,et al.  Isolation of CF cell lines corrected at ΔF508-CFTR locus by SFHR-mediated targeting , 2002, Gene Therapy.

[24]  Gerald B. Pier,et al.  Lung Infections Associated with Cystic Fibrosis , 2002, Clinical Microbiology Reviews.

[25]  W. Guggino,et al.  Accessory Protein Facilitated CFTR-CFTR Interaction, a Molecular Mechanism to Potentiate the Chloride Channel Activity , 2000, Cell.

[26]  N. Bradbury,et al.  E3KARP Mediates the Association of Ezrin and Protein Kinase A with the Cystic Fibrosis Transmembrane Conductance Regulator in Airway Cells* , 2000, The Journal of Biological Chemistry.

[27]  S Grinstein,et al.  The delta F508 mutation decreases the stability of cystic fibrosis transmembrane conductance regulator in the plasma membrane. Determination of functional half-lives on transfected cells. , 1993, The Journal of biological chemistry.

[28]  Pascal Barbry,et al.  Altered chloride ion channel kinetics associated with the ΔF508 cystic fibrosis mutation , 1991, Nature.

[29]  J. Marshall,et al.  Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis , 1990, Cell.

[30]  L. Tsui,et al.  Erratum: Identification of the Cystic Fibrosis Gene: Genetic Analysis , 1989, Science.

[31]  J. Riordan,et al.  The cystic fibrosis transmembrane conductance regulator. , 1993, Annual review of physiology.