Disordered Motifs and Domains in Cell Control - October 11-15, 2014

Disordered Motifs and Domains in Cell Control

Poster Session I

13-POS Board 13 Intrinsically Disordered Cytoplasmic Domains of Two Cytokine Receptors Mediate Novel Interactions with Membranes Gitte W. Haxholm 1 , Louise F. Nikolajsen 1 , Johan G. Olsen 1 , Jacob Fredsted 2 , Flemming H. Larsen 3 , Vincent Goffin 4 , Stine F. Pedersen 2 , Andrew J. Brooks 5 , Michael J. Waters 5 , Birthe B. Kragelund 1 . 1 University of Copenhagen, Copenhagen N, Denmark, 2 University of Copenhagen, Copenhagen, Denmark, 3 University of Copenhagen, Frederiksberg C, Denmark, 4 Inserm, U1151, Paris, France, 5 The University of Queensland, Queensland, Australia. Class 1 cytokine receptors regulate essential biological processes such as metabolism, reproduction and growth, through complex intracellular signaling networks 1,2 . The structural platform for understanding their functions is currently incomplete as structure-function studies of the intracellular domains (ICDs) are critically lacking. We have used nuclear magnetic resonance spectroscopy in combination with other biophysical techniques to present the first comprehensive structural characterization of any cytokine receptor ICD. We show that the ICDs of the human prolactin and growth hormone receptors are intrinsically disordered throughout their entire lengths. We further show that they interact specifically with hallmark lipids of the inner plasma membrane leaflet through conserved hydrophobic and basic motifs resembling immuno T-cell receptor activation motifs (ITAMs). Substituting either the basic or hydrophobic residues resulted in reduced binding to membranes. Based on these results, we propose a model where cytokine receptor ICDs associate with the membrane to confine intracellular signaling at the membrane interface, thereby increasing the efficiency of signaling. Our findings will impact future structure-function studies of cytokine receptors and provide a missing link to address differential signaling implicating the membrane as an active component. 1. Bole-Feysot, C., Goffin, V., Edery, M., Binart, N. & Kelly, P. A. Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. Endocr Rev 19, 225–268 (1998). 2. Brooks, A. J. & Waters, M. J. The growth hormone receptor: mechanism of activation and clinical implications. Nat. Rev. Endocrinol. 6, 515–25 (2010).

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