|1bp3, resolution 2.90Å ()|
THE XRAY STRUCTURE OF A GROWTH HORMONE-PROLACTIN RECEPTOR COMPLEX
The human pituitary hormones, growth hormone (hGH) and prolactin (hPRL), regulate a large variety of physiological processes, among which are growth and differentiation of muscle, bone and cartilage cells, and lactation. These activities are initiated by hormone-receptor binding. The hGH and hPRL receptors (hGHR and hPRLR, respectively) are single-pass transmembrane receptors from class 1 of the haematopoietic receptor superfamily. This classification is based on sequence similarity in their extracellular domains, notably a highly conserved pentapeptide, the so-called 'WSXWS box', the function of which is controversial. All ligands in class 1 activate their respective receptors by clustering mechanisms. In the case of hGH, activation involves receptor homodimerization in a sequential process: the active ternary complex containing one ligand and two receptor molecules is formed by association of a receptor molecule to an intermediate 1:1 complex. hPRL does not bind to the hGH receptor, but hGH binds to both the hGHR and hPRLR, and mutagenesis studies have shown that the receptor-binding sites on hGH overlap. We present here the crystal structure of the 1:1 complex of hGH bound to the extracellular domain of the hPRLR. Comparisons with the hGH-hGHR complex reveal how hGH can bind to the two distinctly different receptor binding surfaces.
The X-ray structure of a growth hormone-prolactin receptor complex., Somers W, Ultsch M, De Vos AM, Kossiakoff AA, Nature. 1994 Dec 1;372(6505):478-81. PMID:7984244
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[SOMA_HUMAN] Defects in GH1 are a cause of growth hormone deficiency isolated type 1A (IGHD1A) [MIM:262400]; also known as pituitary dwarfism I. IGHD1A is an autosomal recessive deficiency of GH which causes short stature. IGHD1A patients have an absence of GH with severe dwarfism and often develop anti-GH antibodies when given exogenous GH. Defects in GH1 are a cause of growth hormone deficiency isolated type 1B (IGHD1B) [MIM:612781]; also known as dwarfism of Sindh. IGHD1B is an autosomal recessive deficiency of GH which causes short stature. IGHD1B patients have low but detectable levels of GH. Dwarfism is less severe than in IGHD1A and patients usually respond well to exogenous GH. Defects in GH1 are the cause of Kowarski syndrome (KWKS) [MIM:262650]; also known as pituitary dwarfism VI. Defects in GH1 are a cause of growth hormone deficiency isolated type 2 (IGHD2) [MIM:173100]. IGHD2 is an autosomal dominant deficiency of GH which causes short stature. Clinical severity is variable. Patients have a positive response and immunologic tolerance to growth hormone therapy.
[SOMA_HUMAN] Plays an important role in growth control. Its major role in stimulating body growth is to stimulate the liver and other tissues to secrete IGF-1. It stimulates both the differentiation and proliferation of myoblasts. It also stimulates amino acid uptake and protein synthesis in muscle and other tissues. [PRLR_HUMAN] This is a receptor for the anterior pituitary hormone prolactin (PRL). Isoform 4 is unable to transduce prolactin signaling. Isoform 6 is unable to transduce prolactin signaling.
About this Structure
- Somers W, Ultsch M, De Vos AM, Kossiakoff AA. The X-ray structure of a growth hormone-prolactin receptor complex. Nature. 1994 Dec 1;372(6505):478-81. PMID:7984244 doi:http://dx.doi.org/10.1038/372478a0
- Duda KM, Brooks CL. Identification of residues outside the two binding sites that are critical for activation of the lactogenic activity of human growth hormone. J Biol Chem. 2003 Jun 20;278(25):22734-9. Epub 2003 Apr 7. PMID:12682073 doi:10.1074/jbc.M212550200
- ↑ Igarashi Y, Ogawa M, Kamijo T, Iwatani N, Nishi Y, Kohno H, Masumura T, Koga J. A new mutation causing inherited growth hormone deficiency: a compound heterozygote of a 6.7 kb deletion and a two base deletion in the third exon of the GH-1 gene. Hum Mol Genet. 1993 Jul;2(7):1073-4. PMID:8364549
- ↑ Takahashi Y, Kaji H, Okimura Y, Goji K, Abe H, Chihara K. Brief report: short stature caused by a mutant growth hormone. N Engl J Med. 1996 Feb 15;334(7):432-6. PMID:8552145 doi:http://dx.doi.org/10.1056/NEJM199602153340704
- ↑ Takahashi Y, Shirono H, Arisaka O, Takahashi K, Yagi T, Koga J, Kaji H, Okimura Y, Abe H, Tanaka T, Chihara K. Biologically inactive growth hormone caused by an amino acid substitution. J Clin Invest. 1997 Sep 1;100(5):1159-65. PMID:9276733 doi:10.1172/JCI119627
- ↑ Petkovic V, Besson A, Thevis M, Lochmatter D, Eble A, Fluck CE, Mullis PE. Evaluation of the biological activity of a growth hormone (GH) mutant (R77C) and its impact on GH responsiveness and stature. J Clin Endocrinol Metab. 2007 Aug;92(8):2893-901. Epub 2007 May 22. PMID:17519310 doi:10.1210/jc.2006-2238
- ↑ Trott JF, Hovey RC, Koduri S, Vonderhaar BK. Alternative splicing to exon 11 of human prolactin receptor gene results in multiple isoforms including a secreted prolactin-binding protein. J Mol Endocrinol. 2003 Feb;30(1):31-47. PMID:12580759