Molecular defects in ion channel regulation in cystic fibrosis predicted from analysis of protein phosphorylation/dephosphorylation
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1Division of Biology and Medicine, Brown University, Providence, RI 02912.
Abstract:
1. Recent discoveries have implicated regulation of an apical membrane chloride channel as site of a defect in cystic fibrosis (CF). The channel fails to respond to stimuli that elevate intracellular cAMP. 2. This paper describes properties of reversible cycles of protein phosphorylation and considers substrate specificity, reactions with model peptides, and space-filling structural models. 3. Mutation of a channel regulatory protein is proposed to involve either: (a) change of phosphorylated serine residue to an unreactive residue, (b) change in a nearby residue that does not affect phosphorylation by cAMP-dependent kinase, but results in dephosphorylation by a different phosphatase, or (c) change in a nearby residue that produces a structure unreactive with cAMP-dependent protein kinase. 4. Perhaps in CF sidechains with branched structures at the beta carbons occur on either side of the phosphorylated serine, like in glycogen phosphorylase, and prohibit reaction of a regulatory protein with cAMP-dependent protein kinase.
Insights
Cystic fibrosis (CF) may stem from defects in a chloride channel regulatory protein. This protein
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- Cystic fibrosis (CF) is linked to defects in apical membrane chloride channels.
- These channels are unresponsive to cyclic adenosine monophosphate (cAMP) stimuli.
Purpose of the Study:
- To explore properties of protein phosphorylation cycles.
- To investigate substrate specificity and structural models of channel regulation.
Main Methods:
- Analysis of reversible protein phosphorylation cycles.
- Consideration of substrate specificity with model peptides.
- Development of space-filling structural models.
Main Results:
- Proposed three mutation models for CF channel regulatory proteins.
- Hypothesized that branched side chains near phosphorylated serine could inhibit kinase interaction.
Conclusions:
- CF defects may involve impaired phosphorylation of chloride channel regulatory proteins.
- Structural changes affecting protein kinase interactions are implicated in CF pathogenesis.