Class 1 cytokine receptors are crucial transmembrane receptors that regulate essential cellular processes such as growth, survival, and proliferation by activating complex signaling pathways. Unlike receptor tyrosine kinases, these receptors lack intrinsic kinase activity due to their intrinsically disordered intracellular domains. Instead, they function as scaffolds, orchestrating the interactions of various signaling molecules. Tight regulation of these binding events is crucial for their signaling specificity.
This study employs an integrative approach combining biophysics, cell biology, and computation to investigate the role of structural disorder in regulating downstream signaling of class 1 cytokine receptors. We demonstrate that structural disorder is a prevalent feature in these receptors, characterized by unique compositional biases and the presence of compacted signaling motif clusters.
Moreover, we unveil direct binding competition between two tyrosine kinases, LYN and JAK2, which determines pathway selectivity in the growth hormone
receptor. Furthermore we identify overlapping binding sites for PI(4,5)P2 and JAK2 in the prolactin receptor, which can simultaneously bind by forming a co-structure involving the receptor’s intracellular domain, PI(4,5)P2, and the FERM-SH2 domain of JAK2. This co-structure adopts distinct conformations
resembling both inactive and active orientations of JAK2. Furthermore, we discover novel binding sites for calmodulin in the growth hormone receptor that coincide with binding sites for the membrane, kinases, degron motifs, phosphorylation sites, and docking sites for accessory signaling molecules. We speculate that calmodulin may have an unidentified regulatory role.
Collectively, the unique attributes of structural disorder provide the intracellular domains of class 1 cytokine receptors with the ability to rapidly interconvert between conformational states in response to environmental cues. Alongside the dynamic nature of the membrane composition and the abundance of posttranslational modifications, these features contribute to the precise orchestration of signalling outcomes. These findings highlight the profound impact of the unique interplay between binding partners and its implications for downstream signalling..