N‑Terminal Phosphorylation of Parathyroid Hormone (PTH) Abolishes Its Receptor Activity
- Publication date
- 2014
- Publisher
Abstract
The
parathyroid hormone (PTH) is an 84-residue peptide, which regulates
the blood Ca<sup>2+</sup> level via GPCR binding and subsequent activation
of intracellular signaling cascades. PTH is posttranslationally phosphorylated
in the parathyroid glands; however, the functional significance of
this processes is not well characterized. In the present study, mass
spectrometric analysis revealed three sites of phosphorylation, and
NMR spectroscopy assigned Ser1, Ser3, and Ser17 as modified sites.
These sites are located at the N-terminus of the hormone, which is
important for receptor recognition and activation. NMR shows further
that the three phosphate groups remotely disturb the α-helical
propensity up to Ala36. An intracellular cAMP accumulation assay elucidated
the biological significance of this phosphorylation because it ablated
the PTH-mediated signaling. Our studies thus shed light on functional
implications of phosphorylation at native PTH as an additional level
of regulation