[PRL_HUMAN] Prolactin acts primarily on the mammary gland by promoting lactation. [PRLR_HUMAN] This is a receptor for the anterior pituitary hormone prolactin (PRL). Isoform 4 is unable to transduce prolactin signaling. Isoform 6 is unable to transduce prolactin signaling.
Human prolactin (hPRL), a member of the family of hematopoietic cytokines, functions as both an endocrine hormone and autocrine/paracrine growth factor. We have previously demonstrated that recognition of the hPRL receptor (hPRLr) depends strongly on solution acidity over the physiologic range from pH 6 &- 8. The hPRL-receptor binding interface contains four histidines, whose protonation is hypothesized to regulate pH-dependent receptor recognition. Here, we systematically dissect its molecular origin by characterizing the consequences of His to Ala mutations on pH-dependent receptor-binding kinetics, site-specific histidine protonation, and high resolution structures of the intermolecular interface. Thermodynamic modeling of the pH dependence to receptor-binding affinity reveals large changes in site-specific protonation constants for a majority of interface histidines upon complexation. Removal of individual His imidazoles reduces these perturbations in protonation constants, which is most likely explained by the introduction of solvent-filled, buried cavities in the crystallographic structures without inducing significant conformational rearrangements.
Two independent histidines, one in human prolactin and one in its receptor, are critical for pH dependent receptor recognition and activation.,Kulkarni MV, Tettamanzi MC, Murphy JW, Keeler C, Myszka DG, Chayen NE, Lolis EJ, Hodsdon ME J Biol Chem. 2010 Sep 30. PMID:20889499
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↑ Trott JF, Hovey RC, Koduri S, Vonderhaar BK. Alternative splicing to exon 11 of human prolactin receptor gene results in multiple isoforms including a secreted prolactin-binding protein. J Mol Endocrinol. 2003 Feb;30(1):31-47. PMID:12580759
↑ Kulkarni MV, Tettamanzi MC, Murphy JW, Keeler C, Myszka DG, Chayen NE, Lolis EJ, Hodsdon ME. Two independent histidines, one in human prolactin and one in its receptor, are critical for pH dependent receptor recognition and activation. J Biol Chem. 2010 Sep 30. PMID:20889499 doi:10.1074/jbc.M110.172072