Orchestration of signaling by structural disorder in class 1 cytokine receptors

Abstract

Background: Class 1 cytokine receptors (C1CRs) are single-pass transmembrane proteins responsible for transmitting signals between the outside and the inside of cells. Remarkably, they orchestrate key biological processes such as proliferation, differentiation, immunity and growth through long disordered intracellular domains (ICDs), but without having intrinsic kinase activity. Despite these key roles, their characteristics remain rudimentarily understood. Methods: The current paper asks the question of why disorder has evolved to govern signaling of C1CRs by reviewing the literature in combination with new sequence and biophysical analyses of chain properties across the family. Results: We uncover that the C1CR-ICDs are fully disordered and brimming with SLiMs. Many of these short linear motifs (SLiMs) are overlapping, jointly signifying a complex regulation of interactions, including network rewiring by isoforms. The C1CR-ICDs have unique properties that distinguish them from most IDPs and we forward the perception that the C1CR-ICDs are far from simple strings with constitutively bound kinases. Rather, they carry both organizational and operational features left uncovered within their disorder, including mechanisms and complexities of regulatory functions. Conclusions: Critically, the understanding of the fascinating ability of these long, completely disordered chains to orchestrate complex cellular signaling pathways is still in its infancy, and we urge a perceptional shift away from the current simplistic view towards uncovering their full functionalities and potential.

On the specificity of protein–protein interactions in the context of disorder

“…Although original work suggested IDPs to be more charged and polar than globular proteins [115][116][117], it is becoming evident that the sequence properties of IDPs are more diverse [118], where some have minimal charges, as seen in the low complexity regions of FUS and hnRNPA1 [119], and others have additional enrichment in proline [120] or glutamine [121,122]. A particular group of IDPs is highly charged with a large surplus of either positive or negative charges, resulting in a large net charge per residue.…”

Order and disorder—An integrative structure of the full-length human growth hormone receptor

“…Since the JAK2 binding site only constitutes ~6% of the ICD, and the STAT5 docking sites are ~200 to 300 residues away from it ( 56 ), conformational changes involving redistribution of the structural ensemble of the long, disordered region need to be achieved in a controlled manner. In addition, the ICD contains many short linear motifs (SLiMs), distributed along the chain in SLiM hotspots ( 8 ), and the space occupied by the free ICD (fig. S5, E and F) may therefore enable room for generation of larger, supramolecular signaling complexes.…”

“…The hGHR is 1 of ~40 receptors belonging to the class 1 cytokine receptor family. The family is topologically similar with a tripartite structure consisting of a folded extracellular domain (ECD), a single-pass transmembrane domain (TMD), and a disordered intracellular domain (ICD) ( 8 , 9 ). A characteristic trait of these receptors is the lack of intrinsic kinase activity, with the ICD, instead, forming a binding platform for a variety of signaling kinases and regulatory proteins ( 8 , 10 ), as well as of certain membrane lipids ( Fig.…”

The thrombopoietin receptor: revisiting the master regulator of platelet production

“…The MPL ICD is predicted to be largely intrinsically disordered in the absence of binding partners[ 41 ]. Tyrosines in the ICD are phosphorylated upon receptor activation ( Figure 1a ) and recruit signal transduction proteins to the membrane and/or within proximity of JAK2.…”