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.
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Research Article|
June 15 2015
Intrinsically disordered cytoplasmic domains of two cytokine receptors mediate conserved interactions with membranes
Gitte W. Haxholm;
Gitte W. Haxholm
*Structural Biology and NMR Laboratory (SBiNLab), Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark
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Louise F. Nikolajsen;
Louise F. Nikolajsen
*Structural Biology and NMR Laboratory (SBiNLab), Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark
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Johan G. Olsen;
Johan G. Olsen
*Structural Biology and NMR Laboratory (SBiNLab), Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark
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Jacob Fredsted;
Jacob Fredsted
†Cell and Developmental Biology, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark
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Flemming H. Larsen;
Flemming H. Larsen
‡Department of Food Science, University of Copenhagen, 1958 Frederiksberg C, Denmark
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Vincent Goffin;
Vincent Goffin
§Inserm, U1151, Institut Necker Enfants Malades (INEM), Equipe “Physiopathologie des hormones PRL/GH”, 75993 Paris Cedex 14, France
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Stine F. Pedersen;
Stine F. Pedersen
†Cell and Developmental Biology, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark
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Andrew J. Brooks;
Andrew J. Brooks
║Institute for Molecular Bioscience, The University of Queensland, Qld 4072, Australia
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Michael J. Waters;
Michael J. Waters
║Institute for Molecular Bioscience, The University of Queensland, Qld 4072, Australia
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Birthe B. Kragelund
Birthe B. Kragelund
1
*Structural Biology and NMR Laboratory (SBiNLab), Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark
1To whom correspondence should be addressed (email bbk@bio.ku.dk).
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Publisher: Portland Press Ltd
Received:
October 06 2014
Revision Received:
March 17 2015
Accepted:
April 07 2015
Accepted Manuscript online:
April 07 2015
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2015 Biochemical Society
2015
Biochem J (2015) 468 (3): 495–506.
Article history
Received:
October 06 2014
Revision Received:
March 17 2015
Accepted:
April 07 2015
Accepted Manuscript online:
April 07 2015
Citation
Gitte W. Haxholm, Louise F. Nikolajsen, Johan G. Olsen, Jacob Fredsted, Flemming H. Larsen, Vincent Goffin, Stine F. Pedersen, Andrew J. Brooks, Michael J. Waters, Birthe B. Kragelund; Intrinsically disordered cytoplasmic domains of two cytokine receptors mediate conserved interactions with membranes. Biochem J 15 June 2015; 468 (3): 495–506. doi: https://doi.org/10.1042/BJ20141243
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