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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