title: Intrinsically disordered cytoplasmic domains of two cytokine receptors mediate conserved interactions with membranes.
abstract: Class 1 cytokine receptors regulate essential biological processes through complex intracellular signalling networks. However, the structural platform for understanding their functions is currently incomplete as structure-function studies of the intracellular domains (ICDs) are critically lacking. The present study provides the first comprehensive structural characterization of any cytokine receptor ICD and demonstrates that the human prolactin (PRL) receptor (PRLR) and growth hormone receptor (GHR) ICDs are intrinsically disordered throughout their entire lengths. We show that they interact specifically with hallmark lipids of the inner plasma membrane leaflet through conserved motifs resembling immuno receptor tyrosine-based activation motifs (ITAMs). However, contrary to the observations made for ITAMs, lipid association of the PRLR and GHR ICDs was shown to be unaccompanied by changes in transient secondary structure and independent of tyrosine phosphorylation. The results of the present study provide a new structural platform for studying class 1 cytokine receptors and may implicate the membrane as an active component regulating intracellular signalling.
authors.affiliation: Structural Biology and NMR Laboratory (SBiNLab), Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Gitte W
authors.initials: GW
authors.lastname: Haxholm
authors.affiliation: Structural Biology and NMR Laboratory (SBiNLab), Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Louise F
authors.initials: LF
authors.lastname: Nikolajsen
authors.affiliation: Structural Biology and NMR Laboratory (SBiNLab), Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Johan G
authors.initials: JG
authors.lastname: Olsen
authors.affiliation: Cell and Developmental Biology, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Jacob
authors.initials: J
authors.lastname: Fredsted
authors.affiliation: Department of Food Science, University of Copenhagen, 1958 Frederiksberg C, Denmark.
authors.forename: Flemming H
authors.initials: FH
authors.lastname: Larsen
authors.affiliation: Inserm, U1151, Institut Necker Enfants Malades (INEM), Equipe "Physiopathologie des hormones PRL/GH", 75993 Paris Cedex 14, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Goffin
authors.affiliation: Cell and Developmental Biology, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Stine F
authors.initials: SF
authors.lastname: Pedersen
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Qld 4072, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Brooks
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Qld 4072, Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Waters
authors.affiliation: Structural Biology and NMR Laboratory (SBiNLab), Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark bbk@bio.ku.dk.
authors.forename: Birthe B
authors.initials: BB
authors.lastname: Kragelund
mesh_terms: D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D002942:Circular Dichroism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010713:Phosphatidylcholines / Q000737:chemistry / Q000378:metabolism; D010718:Phosphatidylserines / Q000737:chemistry / Q000378:metabolism; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011981:Receptors, Prolactin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011986:Receptors, Somatotropin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D053838:Scattering, Small Angle; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D014961:X-Ray Diffraction
chemical_list: D008051:Lipid Bilayers; D010446:Peptide Fragments; D010713:Phosphatidylcholines; D010718:Phosphatidylserines; D011981:Receptors, Prolactin; D011986:Receptors, Somatotropin; D011994:Recombinant Proteins; C050294:1-palmitoyl-2-oleoylglycero-3-phosphoserine; D014443:Tyrosine; C028694:1-palmitoyl-2-oleoylphosphatidylcholine
keywords: growth hormone receptor; immuno T-cell receptor activation motifs; intrinsically disordered protein; membrane interaction; prolactin receptor; signalling