PDBsum entry 2aew

Hormone/growth factor

PDB id: 2aew

Contents

Protein chains

189 a.a. *

188 a.a. *

Waters ×37

* Residue conservation analysis

PDB id:

2aew

Name:

Hormone/growth factor

Title:

A model for growth hormone receptor activation based on subunit rotation within a receptor dimer

Structure:

Growth hormone receptor. Chain: a, b. Fragment: residues 29-233. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.70Å R-factor: 0.257 R-free: 0.302

Authors:

J.J.Adams,W.J.Mckinstry,M.W.Parker,M.J.Waters

Key ref:

R.J.Brown et al. (2005). Model for growth hormone receptor activation based on subunit rotation within a receptor dimer. Nat Struct Mol Biol, 12, 814-821. PubMed id: 16116438 DOI: 10.1038/nsmb977

Date:

24-Jul-05 Release date: 01-Nov-05

Protein chain

P10912  (GHR_HUMAN) -  Growth hormone receptor from Homo sapiens

Seq: 638 a.a.

Struc: 189 a.a.

Protein chain

P10912  (GHR_HUMAN) -  Growth hormone receptor from Homo sapiens

Seq: 638 a.a.

Struc: 188 a.a.

DOI no: 10.1038/nsmb977

Nat Struct Mol Biol 12:814-821 (2005)

PubMed id: 16116438

Model for growth hormone receptor activation based on subunit rotation within a receptor dimer.

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.

ABSTRACT

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.

Selected figure(s)

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).

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.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Mol Biol (2005, 12, 814-821) copyright 2005.

Figures were selected by the author.