The prolactin receptor scaffolds Janus kinase 2 via co-structure formation with phosphoinositide-4,5-bisphosphate

Raul Araya-Secchi, Katrine Bugge, Pernille Seiffert, Amalie Petry, Gitte W. Haxholm, Kresten Lindorff-Larsen, Stine Falsig Pedersen*, Lise Arleth*, Birthe B. Kragelund*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

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 signaling is unclear. Using an integrative approach combining nuclear magnetic resonance spectroscopy, cellular signaling experiments, computational modeling, 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 the 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 signaling on and off. Similar co-structures may be relevant for other non-receptor tyrosine kinases and their receptors.

Original languageEnglish
Article numbere84645
JournaleLife
Volume12
DOIs
StatePublished - 2023

Bibliographical note

Funding Information:
Funder Grant reference number Author Novo Nordisk Fonden NNF18OC0033926 Birthe B Kragelund Novo Nordisk Fonden NNF15OC0016670 Birthe B Kragelund Lundbeckfonden BRAINSTRUC Kresten Lindorff-Larsen The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Publisher Copyright:
© Araya-Secchi et al.

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology

Fingerprint

Dive into the research topics of 'The prolactin receptor scaffolds Janus kinase 2 via co-structure formation with phosphoinositide-4,5-bisphosphate'. Together they form a unique fingerprint.

Cite this