2022
DOI: 10.1101/2022.11.23.517650
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The prolactin receptor scaffolds Janus kinase 2 via co-structure formation with phosphoinositide-4,5-bisphosphate

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 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 intrac… Show more

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Cited by 3 publications
(3 citation statements)
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“…Two interbox α-helices from the JAK2-TMD-ICD model of hEPOR (Figure 5A) overlapped well (RMSD of 0.9 Å) with the same helices observed in the crystal structure of hEPOR ICD peptide in complex with JAK2 FERM-SH2L domains (PDB ID: 6E2Q) [66]. Interbox α-helices found in JAK2-TMD-ICD models of hPRLR and hGHR (Figures 5B and 5C) are supported by NMR studies of ICD-derived peptides in lipid vesicles [67,68]. Additionally, in the AFM models for TPOR and EPOR, a glutamic acid preceding Box2 (E562 in TPOR and E301 in EPOR) bind to the aberrant phosphotyrosine binding pocket of SH2L (Figures 8C, S6), similar to interactions observed in the crystal structure (PDB ID: 6E2Q) [66].…”
Section: Step 3: Modeling Of Monomeric Jak2 Complexes With Receptor T...supporting
confidence: 74%
“…Two interbox α-helices from the JAK2-TMD-ICD model of hEPOR (Figure 5A) overlapped well (RMSD of 0.9 Å) with the same helices observed in the crystal structure of hEPOR ICD peptide in complex with JAK2 FERM-SH2L domains (PDB ID: 6E2Q) [66]. Interbox α-helices found in JAK2-TMD-ICD models of hPRLR and hGHR (Figures 5B and 5C) are supported by NMR studies of ICD-derived peptides in lipid vesicles [67,68]. Additionally, in the AFM models for TPOR and EPOR, a glutamic acid preceding Box2 (E562 in TPOR and E301 in EPOR) bind to the aberrant phosphotyrosine binding pocket of SH2L (Figures 8C, S6), similar to interactions observed in the crystal structure (PDB ID: 6E2Q) [66].…”
Section: Step 3: Modeling Of Monomeric Jak2 Complexes With Receptor T...supporting
confidence: 74%
“…The cytokine receptors GHR and PRLR, as well as the associated JAK2, are known to have specific interactions with PtdIns(4,5) P 2 . Mutations of residues in prolactin receptor (PRLR) that interact with PtdIns(4,5) P 2 impair receptor signalling ( 90, 91 ).Further, Ras (small GTPase) nanoclustering have been shown to be important in oncogenic signalling and attempts to disrupt Ras nanoclusters are being explored as a potential therapeutic strategy ( 92 ). Several of studies have identified Ras interaction with phosphatidylserine in membrane clustering and a recent super-resolution microscopy study defined the nanoscopic spatial association in the membrane between Ras and Phosphatidylserine ( 93 ).…”
Section: Introductionmentioning
confidence: 99%
“…prolactin receptor (PRLR) and its associated JAK2, are known to have specific interactions with phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2 ). Mutations of residues interacting with PI(4,5)P 2 in the PRLR impair receptor signaling [11,12]. For EGFR, although its JM-KD dimerizes and is strongly activated in solution, its activity is abrogated when the same construct is tethered to plasma membrane [10].…”
mentioning
confidence: 99%