title: Biochemical and biophysical analyses of tight junction permeability made of claudin-16 and claudin-19 dimerization.
abstract: The molecular nature of tight junction architecture and permeability is a long-standing mystery. Here, by comprehensive biochemical, biophysical, genetic, and electron microscopic analyses of claudin-16 and -19 interactions--two claudins that play key polygenic roles in fatal human renal disease, FHHNC--we found that 1) claudin-16 and -19 form a stable dimer through cis association of transmembrane domains 3 and 4; 2) mutations disrupting the claudin-16 and -19 cis interaction increase tight junction ultrastructural complexity but reduce tight junction permeability; and 3) no claudin hemichannel or heterotypic channel made of claudin-16 and -19 trans interaction can exist. These principles can be used to artificially alter tight junction permeabilities in various epithelia by manipulating selective claudin interactions. Our study also emphasizes the use of a novel recording approach based on scanning ion conductance microscopy to resolve tight junction permeabilities with submicrometer precision.
authors.affiliation: Department of Internal Medicine-Renal Division, Washington University Medical School, St. Louis, MO 63110 Center for Investigation of Membrane Excitability Diseases, Washington University Medical School, St. Louis, MO 63110.
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Institute of Physiology, University of Marburg, D-35037 Marburg, Germany.
authors.forename: Vijayaram
authors.initials: V
authors.lastname: Renigunta
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, IN 47405.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Internal Medicine-Renal Division, Washington University Medical School, St. Louis, MO 63110 Center for Investigation of Membrane Excitability Diseases, Washington University Medical School, St. Louis, MO 63110.
authors.forename: Abby
authors.initials: A
authors.lastname: Sunq
authors.affiliation: Department of Internal Medicine-Renal Division, Washington University Medical School, St. Louis, MO 63110 Center for Investigation of Membrane Excitability Diseases, Washington University Medical School, St. Louis, MO 63110.
authors.forename: Jinzhi
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine-Renal Division, Washington University Medical School, St. Louis, MO 63110 Center for Investigation of Membrane Excitability Diseases, Washington University Medical School, St. Louis, MO 63110.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: University Children's Hospital, University of Marburg, D-35037 Marburg, Germany.
authors.forename: Aparna
authors.initials: A
authors.lastname: Renigunta
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, IN 47405 jhou@wustl.edu lanbaker@indiana.edu).
authors.forename: Lane A
authors.initials: LA
authors.lastname: Baker
authors.affiliation: Department of Internal Medicine-Renal Division, Washington University Medical School, St. Louis, MO 63110 Center for Investigation of Membrane Excitability Diseases, Washington University Medical School, St. Louis, MO 63110 jhou@wustl.edu lanbaker@indiana.edu).
authors.forename: Jianghui
authors.initials: J
authors.lastname: Hou
mesh_terms: D001671:Biochemistry; D001703:Biophysics; D002463:Cell Membrane Permeability; D057167:Claudins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D055503:Protein Multimerization; D019108:Tight Junctions / Q000737:chemistry* / Q000378:metabolism*
chemical_list: C508912:CLDN19 protein, human; D057167:Claudins; C502010:claudin 16