2aew
From Proteopedia
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|ACTIVITY= | |ACTIVITY= | ||
|GENE= | |GENE= | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY= | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2aew FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2aew OCA], [http://www.ebi.ac.uk/pdbsum/2aew PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2aew RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
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. | 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. | ||
| - | |||
| - | ==Disease== | ||
| - | Known diseases associated with this structure: Increased responsiveness to growth hormone OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600946 600946]], Laron dwarfism OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600946 600946]], Short stature, autosomal dominant, with normal serum growth hormone binding protein OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600946 600946]], Short stature, idiopathic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600946 600946]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: mechanism]] | [[Category: mechanism]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 01:51:41 2008'' |
Revision as of 22:51, 30 March 2008
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| , resolution 2.700Å | |||||||
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
A model for growth hormone receptor activation based on subunit rotation within a receptor dimer
Overview
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.
About this Structure
2AEW is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Model for growth hormone receptor activation based on subunit rotation within a receptor dimer., Brown RJ, Adams JJ, Pelekanos RA, Wan Y, McKinstry WJ, Palethorpe K, Seeber RM, Monks TA, Eidne KA, Parker MW, Waters MJ, Nat Struct Mol Biol. 2005 Sep;12(9):814-21. Epub 2005 Aug 21. PMID:16116438
Page seeded by OCA on Mon Mar 31 01:51:41 2008
