Growth hormone receptor: structure function relationships

Waters, Michael J. and Brooks, Andrew J. (2011) Growth hormone receptor: structure function relationships. Hormone Research in Paediatrics, 76 Supp. 1: 12-16. doi:10.1159/000329138


Author Waters, Michael J.
Brooks, Andrew J.
Title Growth hormone receptor: structure function relationships
Journal name Hormone Research in Paediatrics   Check publisher's open access policy
ISSN 1663-2818
Publication date 2011-07
Sub-type Article (original research)
DOI 10.1159/000329138
Volume 76
Issue Supp. 1
Start page 12
End page 16
Total pages 5
Place of publication Switzerland
Publisher S. Karger AG
Collection year 2012
Language eng
Formatted abstract
Background:
The growth hormone receptor (GHR) was the first class 1 cytokine receptor to be cloned, and it has been studied intensively. The crystal structures of the bound and unbound forms have been solved and the energetic contributions of residues involved in the binding interaction have been quantified. Two receptor subunits bind to opposite sides of the hormone through site 1 and site 2, and a third interaction occurs between receptors in the lower β-sandwich module at site 3. All three interactions are required for receptor activation, which was thought to be a consequence of hormone-induced receptor dimerization. However, substantial data support the existence of a constitutive receptor dimer that interacts via the transmembrane domain (TMD), with receptor activation triggered by a hormone-induced conformational change. Mutagenesis studies and crystal structure data indicate that receptor activation involves a relative rotation and scissor movement of subunits to activate the associated tyrosine kinase, Janus kinase 2 (JAK2). We have recently reported that a second tyrosine kinase, an Src-family kinase, also associates constitutively with the receptor and activates the Ras-extracellular-signal- regulated kinase pathway. Activation of this kinase requires a conformational change in a loop of the lower sandwich module, and a different orientation of the TMDs than needed for JAK2 activation.

Conclusions:

This structural difference could allow differential activation of these two kinases by GH analogues such as I179M human GH.
Keyword Activation mechanism
Constitutive dimer
Growth hormone receptor
Janus kinase 2
Src family kinase
Conformational-Change
Regulatory Step
Dimerization
Pathway
Homodimerization
Activation
Energetics
Binding
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
Institute for Molecular Bioscience - Publications
 
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