Functional regulation of cystic fibrosis transmembrane conductance regulator-containing macromolecular complexes

A small-molecule inhibitor approach

Weiqiang Zhang, Himabindu Penmatsa, Aixia Ren, Chandanamali Punchihewa, Andrew Lemoff, Bing Yan, Naoaki Fujii, Anjaparavanda P. Naren

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

CFTR (cystic fibrosis transmembrane conductance regulator) has been shown to form multiple protein macromolecular complexes with its interacting partners at discrete subcellular microdomains to modulate trafficking, transport and signalling in cells. Targeting protein-protein interactions within these macromolecular complexes would affect the expression or function of the CFTR channel. We specifically targeted the PDZ domain-based LPA2 (type 2 lysophosphatidic acid receptor)-NHERF2 (Na+/H+ exchanger regulatory factor-2) interaction within the CFTR-NHERF2-LPA2- containing macromolecular complexes in airway epithelia and tested its regulatory role on CFTR channel function. We identified a cell-permeable small-molecule compound that preferentially inhibits the LPA2-NHERF2 interaction. We show that this compound can disrupt the LPA2-NHERF2 interaction in cells and thus compromises the integrity of macromolecular complexes. Functionally, it elevates cAMP levels in proximity to CFTR and upregulates its channel activity. The results of the present study demonstrate that CFTR Cl- channel function can be finely tuned by modulating PDZ domain-based protein-protein interactions within the CFTR-containing macromolecular complexes. The present study might help to identify novel therapeutic targets to treat diseases associated with dysfunctional CFTR Cl - channels.

Original languageEnglish (US)
Pages (from-to)451-462
Number of pages12
JournalBiochemical Journal
Volume435
Issue number2
DOIs
StatePublished - Apr 15 2011

Fingerprint

Macromolecular Substances
Cystic Fibrosis Transmembrane Conductance Regulator
Molecules
PDZ Domains
Proteins
Lysophosphatidic Acid Receptors
Multiprotein Complexes
Protein Transport
Cell Communication
Up-Regulation
Epithelium

Keywords

  • Cystic fibrosis transmembrane conductance regulator (CFTR)
  • Na/H exchanger regulatory factor-2 (NHEFR2)
  • PDZ domain
  • Protein-protein interaction
  • Small-molecule inhibitor
  • Type 2 lysophosphatidic acid receptor (LPA)

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Functional regulation of cystic fibrosis transmembrane conductance regulator-containing macromolecular complexes : A small-molecule inhibitor approach. / Zhang, Weiqiang; Penmatsa, Himabindu; Ren, Aixia; Punchihewa, Chandanamali; Lemoff, Andrew; Yan, Bing; Fujii, Naoaki; Naren, Anjaparavanda P.

In: Biochemical Journal, Vol. 435, No. 2, 15.04.2011, p. 451-462.

Research output: Contribution to journalArticle

Zhang, Weiqiang ; Penmatsa, Himabindu ; Ren, Aixia ; Punchihewa, Chandanamali ; Lemoff, Andrew ; Yan, Bing ; Fujii, Naoaki ; Naren, Anjaparavanda P. / Functional regulation of cystic fibrosis transmembrane conductance regulator-containing macromolecular complexes : A small-molecule inhibitor approach. In: Biochemical Journal. 2011 ; Vol. 435, No. 2. pp. 451-462.
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