The prolactin receptor scaffolds Janus kinase 2 via co-structure formation with phosphoinositide-4,5-bisphosphate
Class 1 cytokine receptors transmit signals through the membrane by a single transmembrane helix to an intrinsically disordered cytoplasmic domain that lacks kinase activity. While specific binding to phosphoinositides has been reported for the prolactin receptor (PRLR), the role of lipids in PRLR signalling is unclear. Using an integrative approach combining NMR spectroscopy, cellular signalling experiments, computational modelling and simulation, we demonstrate co-structure formation of the disordered intracellular domain of the human PRLR, the membrane constituent phosphoinositide-4,5-bisphosphate (PI(4,5)P2) and the FERM-SH2 domain of the Janus kinase 2 (JAK2). We find that the complex leads to accumulation of PI(4,5)P2 at the transmembrane helix interface and that mutation of residues identified to interact specifically with PI(4,5)P2 negatively affects PRLR-mediated activation of signal transducer and activator of transcription 5 (STAT5). Facilitated by co-structure formation, the membrane-proximal disordered region arranges into an extended structure. We suggest that the co-structure formed between PRLR, JAK2 and PI(4,5)P2 locks the juxtamembrane disordered domain of the PRLR in an extended structure, enabling signal relay from the extracellular to the intracellular domain upon ligand binding. We find that the co-structure exists in different states which we speculate could be relevant for turning signalling on and off. Similar co-structures may be relevant for other non-receptor tyrosine kinases and their receptors.
All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. The MD data and models together with the scripts used in the trajectory analysis are available on Github at https://github.com/Niels-Bohr-Institute-XNS-StructBiophys/PRLRmodel. NMR chemical shifts for the GHR-ICD-LID1 are deposited in the BioMagResBank under the accession number 51695.
Article and author information
Novo Nordisk Fonden (NNF18OC0033926)
- Birthe B Kragelund
Novo Nordisk Fonden (NNF15OC0016670)
- Birthe B Kragelund
- Kresten Lindorff-Larsen
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Rina Rosenzweig, Weizmann Institute of Science, Israel
- Received: November 2, 2022
- Accepted: May 24, 2023
- Accepted Manuscript published: May 26, 2023 (version 1)
© 2023, Araya-Secchi et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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