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PDBsum entry 2aew
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Hormone/growth factor
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PDB id
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2aew
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References listed in PDB file
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Key reference
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Title
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Model for growth hormone receptor activation based on subunit rotation within a receptor dimer.
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Authors
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R.J.Brown,
J.J.Adams,
R.A.Pelekanos,
Y.Wan,
W.J.Mckinstry,
K.Palethorpe,
R.M.Seeber,
T.A.Monks,
K.A.Eidne,
M.W.Parker,
M.J.Waters.
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Ref.
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Nat Struct Mol Biol, 2005,
12,
814-821.
[DOI no: ]
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PubMed id
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Abstract
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Growth hormone is believed to activate the growth hormone receptor (GHR) by
dimerizing two identical receptor subunits, leading to activation of JAK2 kinase
associated with the cytoplasmic domain. However, we have reported previously
that dimerization alone is insufficient to activate full-length GHR. By
comparing the crystal structure of the liganded and unliganded human GHR
extracellular domain, we show here that there is no substantial change in its
conformation on ligand binding. However, the receptor can be activated by
rotation without ligand by inserting a defined number of alanine residues within
the transmembrane domain. Fluorescence resonance energy transfer (FRET),
bioluminescence resonance energy transfer (BRET) and coimmunoprecipitation
studies suggest that receptor subunits undergo specific transmembrane
interactions independent of hormone binding. We propose an activation mechanism
involving a relative rotation of subunits within a dimeric receptor as a result
of asymmetric placement of the receptor-binding sites on the ligand.
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Figure 1.
Figure 1. Crystal structure of unliganded hGHR ECD. (a) A
ribbon diagram of the unliganded hGHR extracellular domain.
Highlighted areas are the two hormone binding residues Trp104
and Trp169; in purple is the hormone binding region, in magenta
is the flexible linker, and in light blue and green is the
activation lock-and-key region ('dimerization domain'). (b)
Stereo superimposition of C  traces
of hGHR from different crystal structures: molecule A in
unliganded structure (blue), molecule B in unliganded structure
(pink), 1:1 complex (green, PDB entry 1A22 chain B), 2:1 complex
(purple, PDB entry 1HGW chain B), 2:1 complex (red, PDB entry
1HGW chain C).
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Figure 7.
Figure 7. A schematic model of GHR activation. The hormone is
depicted in blue ribbon style and JAK2 as ellipses. The first
diagram shows the unliganded preformed hGHR dimer on the plasma
membrane with the subunits sitting equivalently. In the center
diagram, a hormone molecule binds via site 1 to the left-hand
receptor molecule (receptor 1). This is the structure observed
in the published 1:1 complex. The dimerization domains of each
receptor (located in the C-terminal domains) are far from
complementary because of charge repulsions and steric clashes.
The right-hand diagram shows the structure as observed in the
crystal structure of the published 2:1 complex. On binding to
site 2 of the hormone, the second receptor molecule must move
with respect to the first molecule so that the dimerization
contacts are optimized, involving a rotation and a vertical
movement. This then causes a rotation of the TMD and
juxtamembrane regions, resulting in rotation and activation by
transphosphorylation of the JAK2 molecules bound to box 1, and
the initiation of the GHR signaling cascade. The red line
indicates disulfide bond formation by Cys241, which occurs as a
result of receptor activation28. See also
http://www2.imb.uq.edu.au/groups/waters/hghr.html.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Struct Mol Biol
(2005,
12,
814-821)
copyright 2005.
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