title: PDZ Structure and Implication in Selective Drug Design against Cystic Fibrosis.
abstract: PDZ domains play an essential role in a number of cellular processes by facilitating protein scaffolding and assembly of protein complexes. These domains consist of 80 to 90 amino acids and are found to recognize short C-terminal sequences of target proteins. Protein complex formation between PDZ target molecules can lead to a number of signaling and regulatory cascades that may either promote or inhibit the activation of certain proteins. It has been shown that the interaction of the PDZ domains of NHERF2 with LPA2 plays an inhibitory role on the cystic fibrosis transmembrane conductance regulator (CFTR) by promoting the assembly of a CFTR-NHERF2-LPA2 complex. CFTR regulates chloride ion transport across the epithelial plasma membrane, and individuals possessing CFTR mutations show decreased protein function and consequently, viscous mucus accumulation due to improper fluid transport. This type of ailment is termed cystic fibrosis. Thus, insight to the structure of PDZ domains and how they function to form macromolecular complexes could be therapeutically important in augmenting CFTR channel activity in cystic fibrosis patients. Here we review the PDZ domain family while dissecting their structure, function and implications in CFTR regulation and cystic fibrosis.
authors.forename: Joshua
authors.initials: J
authors.lastname: Holcomb
authors.forename: Nicholas
authors.initials: N
authors.lastname: Spellmon
authors.forename: Laura
authors.initials: L
authors.lastname: Trescott
authors.forename: Fei
authors.initials: F
authors.lastname: Sun
authors.forename: Chunying
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, 540 East Canfield Street, Detroit, Michigan 48201, USA. zyang@med.wayne.edu.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Yang
mesh_terms: D000818:Animals; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D009154:Mutation; D054731:PDZ Domains / Q000187:drug effects*; D010750:Phosphoproteins / Q000737:chemistry* / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000737:chemistry / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000737:chemistry* / Q000378:metabolism
chemical_list: C505032:CFTR protein, human; D010750:Phosphoproteins; D049368:Receptors, Lysophosphatidic Acid; D017923:Sodium-Hydrogen Exchangers; C093376:sodium-hydrogen exchanger regulatory factor; D019005:Cystic Fibrosis Transmembrane Conductance Regulator