title: Structural Basis of a Key Factor Regulating the Affinity between the Zonula Occludens First PDZ Domain and Claudins.
abstract: The molecular seal between epithelial cells, called the tight junction (TJ), is built by several membrane proteins, with claudins playing the most prominent role. The scaffold proteins of the zonula occludens family are required for the correct localization of claudins and hence formation of the TJ. The intracellular C terminus of claudins binds to the N-terminal PDZ domain of zonula occludens proteins (PDZ1). Of the 23 identified human claudin proteins, nine possess a tyrosine at the -6 position. Here we show that the claudin affinity for PDZ1 is dependent on the presence or absence of this tyrosine and that the affinity is reduced if the tyrosine is modified by phosphorylation. The PDZ1 β2-β3 loop undergoes a significant conformational change to accommodate this tyrosine. Cell culture experiments support a regulatory role for this tyrosine. Plasticity has been recognized as a critical property of TJs that allow cell remodeling and migration. Our work provides a molecular framework for how TJ plasticity may be regulated.
authors.affiliation: From the Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, Illinois 60607.
authors.forename: Julian
authors.initials: J
authors.lastname: Nomme
authors.affiliation: From the Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, Illinois 60607.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Antanasijevic
authors.affiliation: From the Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, Illinois 60607.
authors.forename: Michael
authors.initials: M
authors.lastname: Caffrey
authors.affiliation: Laboratory of Tight Junction Structure and Function, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, and.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Van Itallie
authors.affiliation: Laboratory of Tight Junction Structure and Function, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, and.
authors.forename: James M
authors.initials: JM
authors.lastname: Anderson
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina 27599.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Fanning
authors.affiliation: From the Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, Illinois 60607, lavie@uic.edu.
authors.forename: Arnon
authors.initials: A
authors.lastname: Lavie
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D062445:Claudin-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D062446:Claudin-2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D054731:PDZ Domains; D010766:Phosphorylation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D019108:Tight Junctions / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014443:Tyrosine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D062826:Zonula Occludens-1 Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D062445:Claudin-1; D062446:Claudin-2; D062826:Zonula Occludens-1 Protein; D014443:Tyrosine
keywords: ZO-1; claudin; phosphorylation; phosphotyrosine; scaffold protein; structural biology; tight junction