title: Biophysical characterization of interactions between the C-termini of peripheral nerve claudins and the PDZ₁ domain of zonula occludens.
abstract: Our recent study has shown that cellular junctions in myelin and in the epi-/perineruium that encase nerve fibers regulate the permeability of the peripheral nerves. This permeability may affect propagation of the action potential. Direct interactions between the PDZ₁ domain of zonula occludens (ZO₁ or ZO₂) and the C-termini of claudins are known to be crucial for the formation of tight junctions. Using the purified PDZ₁ domain of ZO₂ and a variety of C-terminal mutants of peripheral nerve claudins (claudin-1, claudin-2, claudin-3, claudin-5 in epi-/perineurium; claudin-19 in myelin), we have utilized NMR spectroscopy to determine specific roles of the 3 C-terminal claudin residues (position -2, -1, 0) for their interactions with PDZ₁ of ZO₂. In contrast to the canonical model that emphasizes the importance of residues at the -2 and 0 positions, our results demonstrate that, for peripheral nerve claudins, the residue at position -1 plays a critical role in association with PDZ₁, while the side-chain of residue 0 plays a significant but lesser role. Surprisingly, claudin-19, the most abundant claudin in myelin, exhibited no binding to ZO₂. These findings reveal that the binding mechanism of claudin/ZO in epi-/perineurium is distinct from the canonical interactions between non-ZO PDZ-containing proteins with their ligands. This observation provides the molecular basis for a strategy to develop drugs that target tight junctions in the epi-/perineurium of peripheral nerves.
authors.affiliation: Department of Neurology, Vanderbilt University School of Medicine, USA; Anhui University of Chinese Medicine, Hefei, Anhui, China.
authors.forename: Jiawen
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Neurology, Vanderbilt University School of Medicine, USA.
authors.forename: Dungeng
authors.initials: D
authors.lastname: Peng
authors.affiliation: Department of Neurology, Vanderbilt University School of Medicine, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, USA.
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Center for Structural Biology, Vanderbilt University, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Voehler
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, USA; Center for Structural Biology, Vanderbilt University, USA.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Sanders
authors.affiliation: Department of Neurology, Vanderbilt University School of Medicine, USA; Tennessee Valley Healthcare System (TVHS), Nashville, VA, USA; Center for Human Genetics Research, Vanderbilt University School of Medicine, USA. Electronic address: jun.li.2@vanderbilt.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
mesh_terms: D020816:Amino Acid Motifs; D062445:Claudin-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D062446:Claudin-2 / Q000737:chemistry / Q000378:metabolism; D062465:Claudin-3 / Q000737:chemistry / Q000378:metabolism; D062507:Claudin-5 / Q000737:chemistry / Q000378:metabolism; D057167:Claudins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019906:Nuclear Magnetic Resonance, Biomolecular; D010525:Peripheral Nerves / Q000378:metabolism*; D017433:Protein Structure, Secondary; D062827:Zonula Occludens-2 Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: C508912:CLDN19 protein, human; D062445:Claudin-1; D062446:Claudin-2; D062465:Claudin-3; D062507:Claudin-5; D057167:Claudins; C569046:TJP2 protein, human; C569047:Tjp2 protein, mouse; D062827:Zonula Occludens-2 Protein
keywords: Myelin junction; Myelin permeability; PMP22, peripheral myelin protein-22; PNS, peripheral nervous system; ZO1, zonula occludens-1; ZO2, zonula occludens-2