Spatial control of proton pump H,K-ATPase docking at the apical membrane by phosphorylation-coupled ezrin-syntaxin 3 interaction [Signal Transduction]

October 9th, 2014 by Yu, H., Zhou, J., Takahashi, H., Yao, W., Suzuki, Y., Yuan, X., Yoshimura, S. H., Zhang, Y., Liu, Y., Emmett, N., Bond, V., Wang, D., Ding, X., Takeyasu, K., Yao, X.

The digestive function of the stomach depends on acidification of the gastric lumen. Acid secretion into the lumen is triggered by activation of a cAMP-dependent protein kinase (PKA) cascade, which ultimately results in the insertion of gastric H,K-ATPases into the apical plasma membranes of parietal cells. A coupling protein is ezrin whose phosphorylation at Ser66 by PKA is required for parietal cell activation. However, little is known regarding the molecular mechanism(s) by which ezrin operates in gastric acid secretion. Here we show that phosphorylation of Ser66 induces a conformational change of ezrin which enables its association with syntaxin 3 (Stx3) and provides a spatial cue for H,K-ATPase trafficking. This conformation-dependent association is specific for Stx3 and binding interface is mapped to the N-terminal region. Biochemical analyses show that inhibition of ezrin phosphorylation at Ser66 prevents ezrin-Stx3 association and insertion of H,K-ATPase into the apical plasma membrane of parietal cells. Using atomic force microscopic analyses, our study revealed that phosphorylation of Ser66 induces unfolding of ezrin molecule to allow Stx3 binding to its N-terminus. Given the essential role of Stx3 in polarized secretion, our study presents the first evidence in which phosphorylation-induced conformational rearrangement of ezrin molecule for provides a spatial cue for polarized membrane trafficking in epithelial cells.
  • Posted in Journal of Biological Chemistry, Publications
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