Pernille Seiffert:
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Class 1 cytokine receptors are crucial transmembrane receptors that play vital roles in regulating cell differentiation, growth, and survival, particularly in hematopoietic cell lines. Due to their lack of intrinsic kinase activity, these receptors utilize their intrinsically disordered intracellular domains (ICDs) as scaffolds to activate and coordinate the activation of accessory signaling molecules. This study investigates the role of structural disorder in the ICDs of class 1 cytokine receptors, using prolactin (PRLR) and growth hormone receptors (GHR) as models. The study employs an integrative approach, combining biophysics, cell biology, and computation, to understand how structural disorder aids in orchestrating signal transduction.
The study reveals that the ICDs of class 1 cytokine receptors has a high prevalence of intrinsic disorder and are characterized by unique compositional biases. Further, the ICDs contains clusters of overlapping binding motifs. For GHR direct binding competition between the two primary tyrosine kinases, LYN and JAK2, in the membrane proximal cluster, were found to directly determine pathway selectivity. Additionally, overlapping binding sites for PI(4,5)P2 and JAK2 are identified in the PRLR ICD, leading to the formation of a co-structure involving the ICD, PI(4,5)P2, and the FERM-SH2 domain of JAK2. This complex can adopt distinct conformations resembling both inactive and active receptor states. Lastly, preliminary results indicate novel binding sites for calmodulin in the GHR ICD, coinciding with sites for the membrane, kinases, degron motifs, phosphorylation sites, and additional docking sites for accessory signaling molecules. The precise regulatory role of calmodulin remains unknown and requires further investigation.
In conclusion, the unique attributes of structural disorder enable class 1 cytokine receptors to switch between conformational states in response to environmental cues. Alongside the dynamic membrane composition and post-translational modifications in the ICDs, these features may be crucial for precise signaling orchestration. The study emphasizes the profound impact of the interplay between binding partners and its implications for downstream signaling.