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 by the 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 SLiMs are overlapping, jointly signifying a complex regulation of interactions, including network rewiring by isoforms. The C1CRs-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 a simplistic view towards uncovering their full functionalities.

Assessment of models for calculating the hydrodynamic radius of intrinsically disordered proteins

“…The flow through was collected and used for further purification by reversed-phase chromatography using a Resource RPC column (GE Healthcare), equilibrated in MQ with 0.08% TFA (v/v),and eluted with a linear gradient from 0-100% of 70% acetonitrile (v/v), 0.1% TFA (v/v). NMR experiments were recorded in 20 mM Na 2 HPO 4 /NaH 2 PO 4 , 150 mM NaCl, 10 mM β ME, pH 7.3, 10% (v/v) D 2 O, 0.25 mM DSS, 0.05% (v/v) dioxane, 0.02% NaN 3 and SAXS data in 20 mM Na 2 HPO 4 /NaH 2 PO 4 , 300 mM NaCl, 10x excess of DTT, 2% (v/v) glycerol as described, with protein concentration in the range from 1 to 6 mg mL −1 (39).…”

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 singlepass 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.…”