2aew

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

Structural highlights

2aew is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.7Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

GHR_HUMAN Defects in GHR are a cause of Laron syndrome (LARS) [MIM:262500. A severe form of growth hormone insensitivity characterized by growth impairment, short stature, dysfunctional growth hormone receptor, and failure to generate insulin-like growth factor I in response to growth hormone.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] Defects in GHR may be a cause of idiopathic short stature autosomal (ISSA) [MIM:604271. Short stature is defined by a subnormal rate of growth.[11]

Function

GHR_HUMAN Receptor for pituitary gland growth hormone involved in regulating postnatal body growth. On ligand binding, couples to the JAK2/STAT5 pathway (By similarity). The soluble form (GHBP) acts as a reservoir of growth hormone in plasma and may be a modulator/inhibitor of GH signaling. Isoform 2 up-regulates the production of GHBP and acts as a negative inhibitor of GH signaling.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

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.

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[12]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
88 reviews cite this structure
Medical progress: Acromegaly.
Melmed et al. (2006)
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References

  1. ↑ Amselem S, Duquesnoy P, Attree O, Novelli G, Bousnina S, Postel-Vinay MC, Goossens M. Laron dwarfism and mutations of the growth hormone-receptor gene. N Engl J Med. 1989 Oct 12;321(15):989-95. PMID:2779634
  2. ↑ Kou K, Lajara R, Rotwein P. Amino acid substitutions in the intracellular part of the growth hormone receptor in a patient with the Laron syndrome. J Clin Endocrinol Metab. 1993 Jan;76(1):54-9. PMID:8421103
  3. ↑ Amselem S, Duquesnoy P, Duriez B, Dastot F, Sobrier ML, Valleix S, Goossens M. Spectrum of growth hormone receptor mutations and associated haplotypes in Laron syndrome. Hum Mol Genet. 1993 Apr;2(4):355-9. PMID:8504296
  4. ↑ Edery M, Rozakis-Adcock M, Goujon L, Finidori J, Levi-Meyrueis C, Paly J, Djiane J, Postel-Vinay MC, Kelly PA. Lack of hormone binding in COS-7 cells expressing a mutated growth hormone receptor found in Laron dwarfism. J Clin Invest. 1993 Mar;91(3):838-44. PMID:8450064 doi:http://dx.doi.org/10.1172/JCI116304
  5. ↑ Duquesnoy P, Sobrier ML, Duriez B, Dastot F, Buchanan CR, Savage MO, Preece MA, Craescu CT, Blouquit Y, Goossens M, et al.. A single amino acid substitution in the exoplasmic domain of the human growth hormone (GH) receptor confers familial GH resistance (Laron syndrome) with positive GH-binding activity by abolishing receptor homodimerization. EMBO J. 1994 Mar 15;13(6):1386-95. PMID:8137822
  6. ↑ Sobrier ML, Dastot F, Duquesnoy P, Kandemir N, Yordam N, Goossens M, Amselem S. Nine novel growth hormone receptor gene mutations in patients with Laron syndrome. J Clin Endocrinol Metab. 1997 Feb;82(2):435-7. PMID:9024232
  7. ↑ Walker JL, Crock PA, Behncken SN, Rowlinson SW, Nicholson LM, Boulton TJ, Waters MJ. A novel mutation affecting the interdomain link region of the growth hormone receptor in a Vietnamese girl, and response to long-term treatment with recombinant human insulin-like growth factor-I and luteinizing hormone-releasing hormone analogue. J Clin Endocrinol Metab. 1998 Jul;83(7):2554-61. PMID:9661642
  8. ↑ Wojcik J, Berg MA, Esposito N, Geffner ME, Sakati N, Reiter EO, Dower S, Francke U, Postel-Vinay MC, Finidori J. Four contiguous amino acid substitutions, identified in patients with Laron syndrome, differently affect the binding affinity and intracellular trafficking of the growth hormone receptor. J Clin Endocrinol Metab. 1998 Dec;83(12):4481-9. PMID:9851797
  9. ↑ Enberg B, Luthman H, Segnestam K, Ritzen EM, Sundstrom M, Norstedt G. Characterisation of novel missense mutations in the GH receptor gene causing severe growth retardation. Eur J Endocrinol. 2000 Jul;143(1):71-6. PMID:10870033
  10. ↑ Jorge AA, Souza SC, Arnhold IJ, Mendonca BB. The first homozygous mutation (S226I) in the highly-conserved WSXWS-like motif of the GH receptor causing Laron syndrome: supression of GH secretion by GnRH analogue therapy not restored by dihydrotestosterone administration. Clin Endocrinol (Oxf). 2004 Jan;60(1):36-40. PMID:14678285
  11. ↑ Goddard AD, Covello R, Luoh SM, Clackson T, Attie KM, Gesundheit N, Rundle AC, Wells JA, Carlsson LM. Mutations of the growth hormone receptor in children with idiopathic short stature. The Growth Hormone Insensitivity Study Group. N Engl J Med. 1995 Oct 26;333(17):1093-8. PMID:7565946
  12. ↑ Brown RJ, Adams JJ, Pelekanos RA, Wan Y, McKinstry WJ, Palethorpe K, Seeber RM, Monks TA, Eidne KA, Parker MW, Waters MJ. Model for growth hormone receptor activation based on subunit rotation within a receptor dimer. Nat Struct Mol Biol. 2005 Sep;12(9):814-21. Epub 2005 Aug 21. PMID:16116438 doi:10.1038/nsmb977

Contents


PDB ID 2aew

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