Disordered Motifs and Domains in Cell Control
Poster Session I
22-POS
Board 22
The Intracellular Domain of the Human Growth Hormone Receptor is Intrinsically
Disordered and Interacts with Lipids Characteristic of the Inner Plasma Membrane
Leaflet
Louise F. Nikolajsen
1
, Gitte W. Haxholm
1
, Andrew J. Brooks
2
, Michael J. Waters
2
, Birthe B.
Kragelund
1
.
1
University of Copenhagen, Copenhagen, Denmark,
2
University of Queensland, St. Lucia,
Queensland, Australia.
The growth hormone receptor (GHR) is a single-pass transmembrane protein belonging to the
type I cytokine receptor family. The GHR lacks intrinsic kinase activity and therefore depends
on the activity of constitutively associated Janus Kinase 2 (JAK2) for signaling. GHRs exist as
pre-formed inactive dimers in the membrane and binding of growth hormone (GH) leads to
formation of active ternary 2:1 receptor/hormone complexes. Binding of GH has been shown to
induce conformational changes in the extracellular and transmembrane domains leading to
separation of the lower transmembrane domains and thereby separation of associated JAK2s.
This separation results in release of intermolecular inhibitory interactions between the associated
JAK2s, leading to apposition of kinase domains and signal transduction through the JAK-STAT
pathway. Whereas numerous structures are available of complexes of the extracellular domain,
no structural characterization is available for the intracellular domain (ICD) of the GHR.
Using nuclear magnetic resonance (NMR) spectroscopy we show that the ICD of the human
growth hormone receptor is intrinsically disordered over its entire length without long-range
contacts. We have identified several transiently populated α-helices distributed along the chain,
which are separated by extended structures. Using small unilamellar vesicles (SUVs) and NMR
spectroscopy we have shown that the membrane proximal part of the GHR-ICD specifically
interacts with lipids characteristic of the inner leaflet of the plasma membrane, but not with outer
leaflet lipids. The lipid interaction domain (LID) spans 87 residues with three transient helices
and has an architecture that is analogous to a similar domain identified in the human prolactin
receptor. We propose a role for the LID:membrane interactions in signaling efficiency of the
receptor.
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