Journal ArticleDOI
Model for growth hormone receptor activation based on subunit rotation within a receptor dimer
Richard J. C. Brown,Julian J. Adams,Rebecca A. Pelekanos,Yu Wan,William J. McKinstry,Kathryn Palethorpe,Ruth M. Seeber,Thea A. Monks,Karin A. Eidne,Michael W. Parker,Michael J. Waters +10 more
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TLDR
It is shown that there is no substantial change in the crystal structure of the liganded and unliganded human GHR extracellular domain, and 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 is proposed.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.read more
Citations
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Acromegaly pathogenesis and treatment
TL;DR: Effective control of GH and IGF1 hypersecretion and ablation or stabilization of the pituitary tumor mass lead to improved comorbidities and lowering of mortality rates for this hormonal disorder.
Journal ArticleDOI
JAK/STAT signaling in hematological malignancies
William Vainchenker,William Vainchenker,William Vainchenker,Stefan N. Constantinescu,Stefan N. Constantinescu +4 more
TL;DR: The nature and respective contribution of mutations dysregulating the JAK/STAT pathway in hematological malignancies are discussed and examples in which such mutations drive the disease, contribute to the phenotype, or provide a survival and proliferative advantage are presented.
Journal ArticleDOI
Growth Hormone Regulation of Sex-Dependent Liver Gene Expression
David J. Waxman,Caitlin O’Connor +1 more
TL;DR: The mechanisms whereby GH, via its sex-dependent temporal patterns of pituitary release, activates intracellular signaling leading to the sexually dimorphic transcription of CYPs and other liver-expressed genes are examined.
Journal ArticleDOI
The molecular details of cytokine signaling via the JAK/STAT pathway.
TL;DR: The molecular details of the cytokine‐induced signaling cascade are reviewed and the architectures of the proteins involved are described, including the receptors, kinases, and transcription factors that initiate and propagate signaling and the regulatory proteins that control it.
References
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Journal ArticleDOI
Crystal Structure of Rhodopsin: A G Protein-Coupled Receptor
Krzysztof Palczewski,Takashi Kumasaka,Tetsuya Hori,Craig A. Behnke,H. Motoshima,Brian A. Fox,I. Le Trong,David C. Teller,Tetsuji Okada,Ronald E. Stenkamp,Masaki Yamamoto,Masashi Miyano +11 more
TL;DR: This article determined the structure of rhodopsin from diffraction data extending to 2.8 angstroms resolution and found that the highly organized structure in the extracellular region, including a conserved disulfide bridge, forms a basis for the arrangement of the sevenhelix transmembrane motif.
Journal ArticleDOI
Human Growth Hormone and Extracellular Domain of Its Receptor: Crystal Structure of the Complex
TL;DR: Examination of the 2.8 angstrom crystal structure of the complex between the hormone and the extracellular domain of its receptor (hGHbp) showed that the complex consists of one molecule of growth hormone per two molecules of receptor.
Journal ArticleDOI
The PredictProtein server
TL;DR: PredictProtein is an Internet service for sequence analysis and the prediction of protein structure and function that returns multiple sequence alignments, PROSITE sequence motifs, low-complexity regions (SEG), nuclear localization signals, regions lacking regular structure (NORS) and predictions of secondary structure, solvent accessibility, globular regions, transmembrane helices and functional annotations.
Journal ArticleDOI
Rational design of potent antagonists to the human growth hormone receptor.
Germaine Fuh,Brian C. Cunningham,Rikiro Fukunaga,Shigekazu Nagata,David V. Goeddel,James A. Wells +5 more
TL;DR: Inactive hGH analogs were designed that were potent antagonists to hGH-induced cell proliferation and could be useful for treating clinical conditions of hGH excess, such as acromegaly.
Journal ArticleDOI
Crystallographic evidence for preformed dimers of erythropoietin receptor before ligand activation.
Oded Livnah,Enrico A. Stura,Steven A. Middleton,Dana L. Johnson,Linda K. Jolliffe,Ian A. Wilson +5 more
TL;DR: This model for a preformed dimer on the cell surface provides insights into the organization, activation, and plasticity of recognition of hematopoietic cell surface receptors.