title: N-terminal phosphorylation of parathyroid hormone (PTH) abolishes its receptor activity.
abstract: The parathyroid hormone (PTH) is an 84-residue peptide, which regulates the blood Ca(2+) 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.
authors.affiliation: Institut für Physik, Biophysik and #Mitteldeutsches Zentrum für Struktur und Dynamik der Proteine (MZP), Martin-Luther-Universität Halle-Wittenberg , D-06120 Halle (Saale), Germany.
authors.forename: Amit
authors.initials: A
authors.lastname: Kumar
authors.forename: Mohanraj
authors.initials: M
authors.lastname: Gopalswamy
authors.forename: Clare
authors.initials: C
authors.lastname: Wishart
authors.forename: Mathias
authors.initials: M
authors.lastname: Henze
authors.forename: Lennart
authors.initials: L
authors.lastname: Eschen-Lippold
authors.forename: Dan
authors.initials: D
authors.lastname: Donnelly
authors.forename: Jochen
authors.initials: J
authors.lastname: Balbach
mesh_terms: D000595:Amino Acid Sequence; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D010281:Parathyroid Hormone / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000378:metabolism*
chemical_list: D010281:Parathyroid Hormone; D044168:Receptor, Parathyroid Hormone, Type 1