Biophysical characterization of interactions between the C-termini of peripheral nerve claudins and the PDZ1 domain of zonula occludens

Jiawen Wu, Dungeng Peng, Yang Zhang, Zhenwei Lu, Markus Voehler, Charles R. Sanders, Jun Li

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)87-93
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume459
Issue number1
DOIs
StatePublished - May 30 2015

Keywords

  • Myelin junction
  • Myelin permeability
  • PMP22, peripheral myelin protein-22
  • PNS, peripheral nervous system
  • ZO1, zonula occludens-1
  • ZO2, zonula occludens-2

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Biophysical characterization of interactions between the C-termini of peripheral nerve claudins and the PDZ1 domain of zonula occludens'. Together they form a unique fingerprint.

Cite this