Structural motifs in the extracellular domain of the prolactin receptor govern fold and functionality

摘要: The prolactin receptor (PRLR) is an archetype cytokine receptor. It a single-pass transmembrane with limited complexity that devoid of enzyme activity. Intracellular signaling involves various receptor-associated kinases including Jak2, Erk1/2, Src and Akt. As the PRLR emerging as relevant target in Oncology understanding molecular basis its activation crucial. In frame inter-disciplinary consortium involving biophysicists, structural biologists cell biologists, we have successfully combined complementary approaches such optical nuclear magnetic resonance spectroscopic analyses, X-ray crystallography, surface plasmon cell-based assays to start elucidate features ligand-receptor interaction. However, extracellular domain (ECD) participate transmission hormonal message across membrane and/or selective intracellular cascades remained uncharacterized. two recently published studies, identified residues 146 170 key PRLR-ECD control critical properties basal activity, ligand sensitivity, species specificity, folding, stability turnover. These are close proximity each other proximal network interactions residues, particular within specific residue quartet. Strikingly, these involved in, or to, dimerization interface, suggesting their mechanism action may involve reorientation chains necessary (selectively) disseminate signal from ECD domain. identification this receptors should affect future structure-directed drug development strategies aimed at providing pathway-selective treatment strategies.