5ohd

Putative inactive (dormant) dimeric state of GHR transmembrane domain

spinqualitylabelsall models 5ohd Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5ohd is a 2 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Solution NMR, 20 models 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. 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. 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. Publication Abstract from PubMed BACKGROUND: Prior studies of the human growth hormone receptor (GHR) revealed a distinct role of spatial rearrangements of its dimeric transmembrane domain in signal transduction across membrane. Detailed structural information obtained in the present study allowed elucidating the bases of such rearrangement and provided novel insights into receptor functioning. METHODS: We investigated the dimerization of recombinant TMD fragment GHR254-294 by means of high-resolution NMR in DPC micelles and molecular dynamics in explicit POPC membrane. RESULTS: We resolved two distinct dimeric structures of GHR TMD coexisting in membrane-mimicking micellar environment and providing left- and right-handed helix-helix association via different dimerization motifs. Based on the available mutagenesis data, the conformations correspond to the dormant and active receptor states and are distinguished by cis-trans isomerization of Phe-Pro(266) bond in the transmembrane helix entry. Molecular dynamic relaxations of the structures in lipid bilayer revealed the role of the proline residue in functionally significant rearrangements of the adjacent juxtamembrane region supporting alternation between protein-protein and protein-lipid interactions of this region that can be triggered by ligand binding. Also, the importance of juxtamembrane SS bonding for signal persistency, and somewhat unusual aspects of transmembrane region interaction with water molecules were demonstrated. CONCLUSIONS: Two alternative dimeric structures of GHR TMD attributed to dormant and active receptor states interchange via allosteric rearrangements of transmembrane helices and extracellular juxtamembrane regions that support coordination between protein-protein and protein-lipid interactions. GENERAL SIGNIFICANCE: This study provides a holistic vision of GHR signal transduction across the membrane emphasizing the role of protein-lipid interactions. Structural basis of the signal transduction via transmembrane domain of the human growth hormone receptor.,Bocharov EV, Lesovoy DM, Bocharova OV, Urban AS, Pavlov KV, Volynsky PE, Efremov RG, Arseniev AS Biochim Biophys Acta. 2018 Mar 21;1862(6):1410-1420. doi:, 10.1016/j.bbagen.2018.03.022. PMID:29571748 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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