Phosphorylation of the kinase homology domain is essential for activation of the A-type natriuretic peptide receptor.

Molecular and Cellular Biology
Lincoln R Potter, T Hunter

Abstract

Natriuretic peptide receptor A (NPR-A) is the biological receptor for atrial natriuretic peptide (ANP). Activation of the NPR-A guanylyl cyclase requires ANP binding to the extracellular domain and ATP binding to a putative site within its cytoplasmic region. The allosteric interaction of ATP with the intracellular kinase homology domain (KHD) is hypothesized to derepress the carboxyl-terminal guanylyl cyclase catalytic domain, resulting in the synthesis of the second messenger, cyclic GMP. Here, we show that phosphorylation of the KHD is essential for receptor activation. Using a combination of phosphopeptide mapping techniques, we have identified six residues within the ATP-binding domain (S497, T500, S502, S506, S510, and T513) which are phosphorylated when NPR-A is expressed in HEK 293 cells. Mutation of any one of these Ser or Thr residues to Ala caused reductions in the receptor phosphorylation state, the number and pattern of phosphopeptides observed in tryptic maps, and ANP-dependent guanylyl cyclase activity. The reductions were not explained by decreases in NPR-A protein levels, as indicated by immunoblot analysis and determinations of cyclase activity in the presence of detergent. Conversion of Ser-497 to Ala resulte...Continue Reading

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Citations

Jul 12, 2003·The Journal of Biological Chemistry·Nathan AirhartMichael Silberbach
Jun 6, 2009·Annual Review of Biochemistry·Mary Katherine Tarrant, Philip A Cole
Aug 20, 2014·The Journal of Cell Biology·Magdalena PichloUrsel Collienne
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May 3, 2002·European Journal of Biochemistry·Inez Ruiz-StewartScott A Waldman

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