6ni3
From Proteopedia
B2V2R-Gs protein subcomplex of a GPCR-G protein-beta-arrestin mega-complex
Structural highlights
Disease[GNAS2_HUMAN] Pseudopseudohypoparathyroidism;Pseudohypoparathyroidism type 1A;Progressive osseous heteroplasia;Polyostotic fibrous dysplasia;Monostotic fibrous dysplasia;Pseudohypoparathyroidism type 1C;Pseudohypoparathyroidism type 1B;McCune-Albright syndrome. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. Most affected individuals have defects in methylation of the gene. In some cases microdeletions involving the STX16 appear to cause loss of methylation at exon A/B of GNAS, resulting in PHP1B. Paternal uniparental isodisomy have also been observed. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. Function[GNAS2_HUMAN] Guanine nucleotide-binding proteins (G proteins) function as transducers in numerous signaling pathways controlled by G protein-coupled receptors (GPCRs) (PubMed:17110384). Signaling involves the activation of adenylyl cyclases, resulting in increased levels of the signaling molecule cAMP (PubMed:26206488, PubMed:8702665). GNAS functions downstream of several GPCRs, including beta-adrenergic receptors (PubMed:21488135). Stimulates the Ras signaling pathway via RAPGEF2 (PubMed:12391161).[1] [2] [3] [4] [5] [GBG2_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction (By similarity). [GBB1_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.[6] Publication Abstract from PubMedClassically, G-protein-coupled receptors (GPCRs) are thought to activate G protein from the plasma membrane and are subsequently desensitized by beta-arrestin (beta-arr). However, some GPCRs continue to signal through G protein from internalized compartments, mediated by a GPCR-G protein-beta-arr 'megaplex'. Nevertheless, the molecular architecture of the megaplex remains unknown. Here, we present its cryo-electron microscopy structure, which shows simultaneous engagement of human G protein and bovine beta-arr to the core and phosphorylated tail, respectively, of a single active human chimeric beta2-adrenergic receptor with the C-terminal tail of the arginine vasopressin type 2 receptor (beta2V2R). All three components adopt their canonical active conformations, suggesting that a single megaplex GPCR is capable of simultaneously activating G protein and beta-arr. Our findings provide a structural basis for GPCR-mediated sustained internalized G protein signaling. Structure of an endosomal signaling GPCR-G protein-beta-arrestin megacomplex.,Nguyen AH, Thomsen ARB, Cahill TJ 3rd, Huang R, Huang LY, Marcink T, Clarke OB, Heissel S, Masoudi A, Ben-Hail D, Samaan F, Dandey VP, Tan YZ, Hong C, Mahoney JP, Triest S, Little J 4th, Chen X, Sunahara R, Steyaert J, Molina H, Yu Z, des Georges A, Lefkowitz RJ Nat Struct Mol Biol. 2019 Nov 18. pii: 10.1038/s41594-019-0330-y. doi:, 10.1038/s41594-019-0330-y. PMID:31740855[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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