Intrinsically disordered cytoplasmic domains of two cytokine receptors mediate conserved interactions with membranes

• Published in: Biochemical journal Vol. 468; no. 3; p. 495
• Main Authors: Haxholm, Gitte W, Nikolajsen, Louise F, Olsen, Johan G, Fredsted, Jacob, Larsen, Flemming H, Goffin, Vincent, Pedersen, Stine F, Brooks, Andrew J, Waters, Michael J, Kragelund, Birthe B
• Format: Journal Article
• Language: English
• Published: England 15-06-2015
• Subjects: Cell Line; Cell Membrane - chemistry; Cell Membrane - metabolism; Circular Dichroism; Humans; Hydrophobic and Hydrophilic Interactions; Lipid Bilayers - chemistry; Lipid Bilayers - metabolism; Models, Molecular; Nuclear Magnetic Resonance, Biomolecular; Peptide Fragments - chemistry; Peptide Fragments - genetics; Peptide Fragments - metabolism; Phosphatidylcholines - chemistry; Phosphatidylcholines - metabolism; Phosphatidylserines - chemistry; Phosphatidylserines - metabolism; Protein Folding; Protein Structure, Tertiary; Receptors, Prolactin - chemistry; Receptors, Prolactin - genetics; Receptors, Prolactin - metabolism; Receptors, Somatotropin - chemistry; Receptors, Somatotropin - genetics; Receptors, Somatotropin - metabolism; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Scattering, Small Angle; Signal Transduction; Tyrosine - metabolism; X-Ray Diffraction; prolactin receptor; immuno T-cell receptor activation motifs; intrinsically disordered protein; growth hormone receptor; signalling; membrane interaction
• ISSN: 1470-8728
• DOI: 10.1042/BJ20141243

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.