The Tertiary Structure and Backbone Dynamics of Human Prolactin

Keeler, Camille; Dannies, Priscilla S.; Hodsdon, Michael E.

doi:10.1016/s0022-2836(03)00367-x

Cited by 80 publications

(69 citation statements)

References 66 publications

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“…This spectrum appears similar to the 3D 13 C-NOESY-HSQC recorded at pH 8 that was used for NOE assignment in the present work. Although we have not performed an exhaustive analysis of the pH 6.8 NOESY-HSQC spectrum, none of the NOEs reported by Keeler et al, 20 which we had not already found in our analysis of the pH 8 spectrum, were found in the spectrum recorded at pH 6.8 ( Figure 4(b)). …”

Section: Discussion Comparison To 1n9dmentioning

confidence: 54%

“…Alignment of the present structure at pH 8 (PDB entry 1RW5) with the recently published solution structure of human prolactin at pH 6.8, (PDB entry 1N9D), 20 shows significant and unexpected differences in the geometry, arrangement and orientation of the well-ordered parts of the molecule (Figure 3). Especially distinct are the differences in the regularity of the long helices and the orientation of the short helix 1 00 .…”

Section: Discussion Comparison To 1n9dmentioning

confidence: 62%

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Solution Structure of Human Prolactin

Teilum

Hoch

Goffin

et al. 2005

Journal of Molecular Biology

114

110

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We report the solution structure of human prolactin determined by NMR spectroscopy. Our result is a significant improvement over a previous structure in terms of number and distribution of distance restraints, regularity of secondary structure, and potential energy. More significantly, the structure is sufficiently different that it leads to different conclusions regarding the mechanism of receptor activation and initiation of signal transduction. Here, we compare the structure of unbound prolactin to structures of both the homologue ovine placental lactogen and growth hormone. The structures of unbound and receptor bound prolactin/ placental lactogen are similar and no noteworthy structural changes occur upon receptor binding. The observation of enhanced binding at the second receptor site when the first site is occupied has been widely interpreted to indicate conformational change induced by binding the first receptor. However, our results indicate that this enhanced binding at the second site could be due to receptor-receptor interactions or some other free energy sources rather than conformational change in the hormone. Titration of human prolactin with the extracellular domain of the human prolactin receptor was followed by NMR, gel filtration and electrophoresis. Both binary and ternary hormone-receptor complexes are clearly detectable by gel filtration and electrophoresis. The binary complex is not observable by NMR, possibly due to a dynamic equilibrium in intermediate exchange within the complex. The ternary complex of one hormone molecule bound to two receptor molecules is on the contrary readily detectable by NMR. This is in stark contrast to the widely held view that the ternary prolactinreceptor complex is only transiently formed. Thus, our results lead to improved understanding of the prolactin-prolactin receptor interaction.

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Section: Discussion Comparison To 1n9dmentioning

confidence: 54%

Section: Discussion Comparison To 1n9dmentioning

confidence: 62%

Solution Structure of Human Prolactin

Teilum

Hoch

Goffin

et al. 2005

Journal of Molecular Biology

114

110

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“…Corresponding 1:1 or 1:2 complex structures of the PRL/PRLR system have not been reported, and experimental structures of free PRL molecules became available only quite recently. The NMR derived solution structure of wtPRL (14,15) and the recently published x-ray structure of a PRLR antagonist, ⌬1-9-PRL-G129R (16), represent major contributions to the structural characterization of the PRL molecule.…”

Section: Prolactin (Prl)mentioning

confidence: 99%

Crystal Structure of a Prolactin Receptor Antagonist Bound to the Extracellular Domain of the Prolactin Receptor

Svensson

Bondensgaard

Nørskov-Lauritsen

et al. 2008

Journal of Biological Chemistry

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The crystal structure of the complex between an N-terminally truncated G129R human prolactin (PRL) variant and the extracellular domain of the human prolactin receptor (PRLR) was determined at 2.5 Å resolution by x-ray crystallography. This structure represents the first experimental structure reported for a PRL variant bound to its cognate receptor. The binding of PRL variants to the PRLR extracellular domain was furthermore characterized by the solution state techniques, hydrogen exchange mass spectrometry, and NMR spectroscopy. Compared with the binding interface derived from mutagenesis studies, the structural data imply that the definition of PRL binding site 1 should be extended to include residues situated in the N-terminal part of loop 1 and in the C terminus. Prolactin (PRL)4 is a protein hormone secreted by the anterior pituitary in vertebrates and possesses physiological functions of remarkable diversity, including effects on reproduction, lactation, and growth. PRL belongs to a family of homologous proteins comprising PRL, growth hormone (GH), and placental lactogen (PL). The biological effects associated with this cytokine family are mediated by two distinct classes of cell surface receptors, the PRL receptors (PRLR) and the GH receptors (GHR). The PRL/PL/GH biology is governed by a delicate balance between receptor cross-reactivity and selectivity; PRL and PL bind selectively to PRLR, whereas GH is capable of binding both PRLR and GHR.After being proposed more than a decade ago (1), hormoneinduced receptor dimerization became generally accepted as the model for cytokine receptor activation. For the PRL family members, the model describes the signaling molecular entity as a ternary complex between one hormone molecule and a receptor homodimer assembled in a strictly sequential and hormonedependent fashion; first the hormone ligand engages via binding site 1 (BS1) in high affinity binding to one receptor chain forming a 1:1 hormone-receptor complex. This complex constitutes the template for binding a second, identical receptor molecule via binding site 2 (BS2), resulting in the active 1:2 complex. However, the model has been challenged by an increasing body of experimental evidence, initially reported for the homologous human erythropoietin receptor (2) and later for GHR (3) and PRLR (4). These studies suggest that preformed, inactive dimers exist in the absence of hormone. Thus, receptor dimerization is a necessary but not sufficient event for receptor activation and, notably, not strictly ligand-dependent. For both human erythropoietin receptor (5) and GHR (3), mechanistic models have been proposed, where receptor activation involves relative rotations and movements of receptor subunits induced by hormone binding. Allosteric reorganization of the intracellular receptor domains brings associated JAK2 kinases into close proximity, allowing their activation by cross-phosphorylation. This initial activation step triggers a cascade of molecular events leading to the functional receptor response (6).The...

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“…Detailed analysis of the changes that occur during the episodes of rapid coevolution of PRL and its receptor can potentially indicate whether such changes are likely to alter the specificity of hormone-receptor interaction, but in the absence of a three-dimensional structure for any homologous PRL-PRLR complex, such analysis would be difficult and over-speculative. Analysis of the changes that occur in PRL during the burst of evolution in primates in light of the three-dimensional structure of human PRL (Keeler et al 2003) indicates that none of these occurs in binding site 1 (Wallis et al 2005), but binding site 2 is not well-defined. This contrasts with the situation for primate growth hormone, where there are many substitutions in both sites 1 and 2 during the episode of rapid evolution (Liu et al 2001, Wallis et al 2001.…”

Section: Biological Significance Of Episodic Evolution Of Prlr and Itmentioning

confidence: 99%

Episodic evolution of prolactin receptor gene in mammals: coevolution with its ligand

Wallis²,

Zhang³

2005

Journal of Molecular Endocrinology

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Divergence of proteins in signaling pathways requires ligand and receptor coevolution to maintain or improve binding affinity and/or specificity. In this paper we show a clear case of coevolution between the prolactin (PRL) gene and its receptor (prolactin receptor, PRLR) in mammals. First we observed episodic evolution of the extracellular and intracellular domains of the PRLR, which is closely consistent with that seen in PRL. Correlated evolution was demonstrated both between PRL and its receptor and between the two domains of the PRLR using Pearson's correlation coefficient. On comparing the ratio of the nonsynonymous substitution rate to synonymous substitution rate ( =d N /d S ) for each branch of the star phylogeny of mammalian PRLRs, separately for the extracellular domain (ECD) and the transmembrane domain/intracellular domain (TMD/ICD), we observed a lower ratio for ECD than TMD/ICD along those branches leading to pig, dog and rabbit but a higher ratio for ECD than TMD/ICD on the branches leading to primates, rodents and ruminants, on which bursts of rapid evolution were observed. These observations can be best explained by coevolution between PRL and its receptor and between the two domains of the PRLR.

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The Tertiary Structure and Backbone Dynamics of Human Prolactin

Cited by 80 publications

References 66 publications

Solution Structure of Human Prolactin

Solution Structure of Human Prolactin

Crystal Structure of a Prolactin Receptor Antagonist Bound to the Extracellular Domain of the Prolactin Receptor

Episodic evolution of prolactin receptor gene in mammals: coevolution with its ligand

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