The Interaction between Syntaxin 1A and Cystic Fibrosis Transmembrane Conductance Regulator Cl− Channels Is Mechanistically Distinct from Syntaxin 1A-SNARE Interactions*

Syntaxin 1A binds to and inhibits epithelial cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channels and synaptic Ca2+ channels in addition to participating in SNARE complex assembly and membrane fusion. We exploited the isoform-specific nature of the interaction between syntaxin 1A and CFTR to identify residues in the H3 domain of this SNARE (SNARE motif) that influence CFTR binding and regulation. Mutating isoform-specific residues that map to the surface of syntaxin 1A in the SNARE complex led to the identification of two sets of hydrophilic residues that are important for binding to and regulating CFTR channels or for binding to the syntaxin regulatory protein Munc-18a. None of these mutations affected syntaxin 1A binding to other SNAREs or the assembly and stability of SNARE complexes in vitro. Conversely, the syntaxin 1A-CFTR interaction was unaffected by mutating hydrophobic residues in the H3 domain that influence SNARE complex stability and Ca2+ channel regulation. Thus, CFTR channel regulation by syntaxin 1A involves hydrophilic interactions that are mechanistically distinct from the hydrophobic interactions that mediate SNARE complex formation and Ca2+ channel regulation by this t-SNARE.

• Publication year

  2003

• Venue

  Journal of Biological Chemistry

• Publication date

  2003-01-31

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1074/jbc.M211790200PMID 12446681
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• CFTR channel regulation by syntaxin 1A depends on hydrophilic interactions that are mechanistically distinct from the hydrophobic interactions underlying SNARE complex formation.

  Confidence 0.97

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• Mutations of hydrophobic H3-domain residues do not alter the syntaxin 1A-CFTR interaction.

  Confidence 0.94

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• Isoform-specific residues on the surface of syntaxin 1A's H3 domain define two hydrophilic residue sets, one important for CFTR channel binding and regulation and another for Munc-18a binding.

  Confidence 0.96

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review

• cftr cl− channels

  ion channel

  Epithelial chloride channels formed by CFTR and used here as the interaction and regulation target of syntaxin 1A.

  Aliases: CFTR channels

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• h3 domain

  protein domain

  The C-terminal SNARE-motif region of syntaxin 1A that was mutagenized in this work.

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• hydrophilic residues

  residue set

  Polar amino acid positions on the surface of syntaxin 1A's H3 domain targeted by mutagenesis.

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• hydrophobic residues

  residue set

  Nonpolar amino acid positions in syntaxin 1A's H3 domain that were mutated to test their contribution to syntaxin-dependent interactions.

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• munc-18a

  regulatory protein

  A syntaxin regulatory protein tested here for its interaction with syntaxin 1A.

  Aliases: Munc18a

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• snare complex

  protein complex

  The membrane-fusion protein complex assembled from syntaxin and partner SNAREs.

  Aliases: SNARE complexes

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• syntaxin 1a

  protein

  A syntaxin family membrane SNARE protein examined here for residues that mediate CFTR binding and other partner interactions.

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review

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