A combined computational and structural model of the full-length human prolactin receptor

The prolactin receptor is an archetype member of the class I cytokine receptor family, comprising receptors with fundamental functions in biology as well as key drug targets. Structurally, each of these receptors represent an intriguing diversity, providing an exceptionally challenging target for structural biology. Here, we access the molecular architecture of the monomeric human prolactin receptor by combining experimental and computational efforts. We solve the NMR structure of its transmembrane domain in micelles and collect structural data on overlapping fragments of the receptor with small-angle X-ray scattering, native mass spectrometry and NMR spectroscopy. Along with previously published data, these are integrated by molecular modelling to generate a full receptor structure. The result provides the first full view of a class I cytokine receptor, exemplifying the architecture of more than 40 different receptor chains, and reveals that the extracellular domain is merely the tip of a molecular iceberg

Cytokine receptors

Cytokine receptors initiate intracellular signalling that regulate a diverse range of biological and medically important functions including metabolism control, neural stem cell activation, inflammatory responses, bone development, as well as blood cell and immune cell development and growth. The unifying feature of these receptors is their ability to activate the JAK-STAT pathway, however they are grouped into two structurally related classes, known as class I and class II. Class I cytokine receptors has over 30 members including receptors for erythropoietin (EPO), prolactin (PRL), growth hormone (GH), thrombopoietin (TPO), leptin, (LEP), granulocyte-macrophage colony-stimulating factor (GM-CSF), leukaemia inhibitory factor (LIF), interleukin-3 (IL-3), IL-5, IL-6, and IL-7. The Class I cytokine receptor family includes the interferon receptors, IL-10 receptor, and number of more recently discovered cytokine receptors for IL-19, IL-20, IL-22, IL-24, IL-26, and IL-29. This chapter will review the structure, activation mechanism, and signalling of cytokine receptors