Syntaxin 1A inhibits CFTR chloride channels by means of domain-specific protein–protein interactions

Previously we showed that the functional activity of the epithelial chloride channel that is encoded by the cystic fibrosis gene (CFTR) is reciprocally modulated by two components of the vesicle fusion machinery, syntaxin 1A and Munc-18. Here we report that syntaxin 1A inhibits CFTR chloride channel...

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Auteurs principaux: Naren, Anjaparavanda P., Quick, Michael W., Collawn, James F., Nelson, Deborah J., Kirk, Kevin L.
Format: Article
Langue:en
Publié: The National Academy of Sciences 1998
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Biological Sciences
Accès en ligne:https://ncbi.nlm.nih.gov/pmc/articles/PMC28005/
https://ncbi.nlm.nih.gov/pubmed/9724814
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spelling pubmed-280052001-03-17 Syntaxin 1A inhibits CFTR chloride channels by means of domain-specific protein–protein interactions Naren, Anjaparavanda P. Quick, Michael W. Collawn, James F. Nelson, Deborah J. Kirk, Kevin L. Proc Natl Acad Sci U S A Biological Sciences Previously we showed that the functional activity of the epithelial chloride channel that is encoded by the cystic fibrosis gene (CFTR) is reciprocally modulated by two components of the vesicle fusion machinery, syntaxin 1A and Munc-18. Here we report that syntaxin 1A inhibits CFTR chloride channels by means of direct and domain-specific protein–protein interactions. Syntaxin 1A stoichiometrically binds to the N-terminal cytoplasmic tail of CFTR, and this binding is blocked by Munc-18. The modulation of CFTR currents by syntaxin 1A is eliminated either by deletion of this tail or by injecting this tail as a blocking peptide into coexpressing Xenopus oocytes. The CFTR binding site on syntaxin 1A maps to the third predicted helical domain (H3) of this membrane protein. Moreover, CFTR Cl(−) currents are effectively inhibited by a minimal syntaxin 1A construct (i.e., the membrane-anchored H3 domain) that cannot fully substitute for wild-type syntaxin 1A in membrane fusion reactions. We also show that syntaxin 1A binds to and inhibits the activities of disease-associated mutants of CFTR, and that the chloride current activity of recombinant ΔF508 CFTR (i.e., the most common cystic fibrosis mutant) can be potentiated by disrupting its interaction with syntaxin 1A in cultured epithelial cells. Our results provide evidence for a direct physical interaction between CFTR and syntaxin 1A that limits the functional activities of normal and disease-associated forms of this chloride channel. The National Academy of Sciences 1998-09-01 /pmc/articles/PMC28005/ /pubmed/9724814 Text en Copyright © 1998, The National Academy of Sciences
institution US National Library of Medicine
collection PubMed Central
language en
format Article
topic Biological Sciences
spellingShingle Biological Sciences
Naren, Anjaparavanda P.
Quick, Michael W.
Collawn, James F.
Nelson, Deborah J.
Kirk, Kevin L.
Syntaxin 1A inhibits CFTR chloride channels by means of domain-specific protein–protein interactions
description Previously we showed that the functional activity of the epithelial chloride channel that is encoded by the cystic fibrosis gene (CFTR) is reciprocally modulated by two components of the vesicle fusion machinery, syntaxin 1A and Munc-18. Here we report that syntaxin 1A inhibits CFTR chloride channels by means of direct and domain-specific protein–protein interactions. Syntaxin 1A stoichiometrically binds to the N-terminal cytoplasmic tail of CFTR, and this binding is blocked by Munc-18. The modulation of CFTR currents by syntaxin 1A is eliminated either by deletion of this tail or by injecting this tail as a blocking peptide into coexpressing Xenopus oocytes. The CFTR binding site on syntaxin 1A maps to the third predicted helical domain (H3) of this membrane protein. Moreover, CFTR Cl(−) currents are effectively inhibited by a minimal syntaxin 1A construct (i.e., the membrane-anchored H3 domain) that cannot fully substitute for wild-type syntaxin 1A in membrane fusion reactions. We also show that syntaxin 1A binds to and inhibits the activities of disease-associated mutants of CFTR, and that the chloride current activity of recombinant ΔF508 CFTR (i.e., the most common cystic fibrosis mutant) can be potentiated by disrupting its interaction with syntaxin 1A in cultured epithelial cells. Our results provide evidence for a direct physical interaction between CFTR and syntaxin 1A that limits the functional activities of normal and disease-associated forms of this chloride channel.
author Naren, Anjaparavanda P.
Quick, Michael W.
Collawn, James F.
Nelson, Deborah J.
Kirk, Kevin L.
author_facet Naren, Anjaparavanda P.
Quick, Michael W.
Collawn, James F.
Nelson, Deborah J.
Kirk, Kevin L.
author_sort Naren, Anjaparavanda P.
title Syntaxin 1A inhibits CFTR chloride channels by means of domain-specific protein–protein interactions
title_short Syntaxin 1A inhibits CFTR chloride channels by means of domain-specific protein–protein interactions
title_full Syntaxin 1A inhibits CFTR chloride channels by means of domain-specific protein–protein interactions
title_fullStr Syntaxin 1A inhibits CFTR chloride channels by means of domain-specific protein–protein interactions
title_full_unstemmed Syntaxin 1A inhibits CFTR chloride channels by means of domain-specific protein–protein interactions
title_sort syntaxin 1a inhibits cftr chloride channels by means of domain-specific protein–protein interactions
publisher The National Academy of Sciences
publisher_facet The National Academy of Sciences
publishDate 1998
url https://ncbi.nlm.nih.gov/pmc/articles/PMC28005/
https://ncbi.nlm.nih.gov/pubmed/9724814
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