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Cryo-EM structure of the glucagon receptor bound to beta-arrestin 1 in ligand-free state
Structural highlights
DiseasePROC_HUMAN Defects in PROC are the cause of thrombophilia due to protein C deficiency, autosomal dominant (THPH3) [MIM:176860. A hemostatic disorder characterized by impaired regulation of blood coagulation and a tendency to recurrent venous thrombosis. However, many adults with heterozygous disease may be asymptomatic. Individuals with decreased amounts of protein C are classically referred to as having type I protein C deficiency and those with normal amounts of a functionally defective protein as having type II deficiency.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] Defects in PROC are the cause of thrombophilia due to protein C deficiency, autosomal recessive (THPH4) [MIM:612304. A hemostatic disorder characterized by impaired regulation of blood coagulation and a tendency to recurrent venous thrombosis. It results in a thrombotic condition that can manifest as a severe neonatal disorder or as a milder disorder with late-onset thrombophilia. The severe form leads to neonatal death through massive neonatal venous thrombosis. Often associated with ecchymotic skin lesions which can turn necrotic called purpura fulminans, this disorder is very rare.V2R_HUMAN Nephrogenic syndrome of inappropriate antidiuresis;Inappropriate antidiuretic hormone secretion syndrome;Nephrogenic diabetes insipidus. 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. FunctionPROC_HUMAN Protein C is a vitamin K-dependent serine protease that regulates blood coagulation by inactivating factors Va and VIIIa in the presence of calcium ions and phospholipids.V2R_HUMAN Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. Involved in renal water reabsorption.[15] GLR_HUMAN This is a receptor for glucagon which plays a central role in regulating the level of blood glucose by controlling the rate of hepatic glucose production and insulin secretion. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase and also a phosphatidylinositol-calcium second messenger system.HEMA_I75A3 Binds to sialic acid-containing receptors on the cell surface, bringing about the attachment of the virus particle to the cell. This attachment induces virion internalization of about two third of the virus particles through clathrin-dependent endocytosis and about one third through a clathrin- and caveolin-independent pathway. Plays a major role in the determination of host range restriction and virulence. Class I viral fusion protein. Responsible for penetration of the virus into the cell cytoplasm by mediating the fusion of the membrane of the endocytosed virus particle with the endosomal membrane. Low pH in endosomes induces an irreversible conformational change in HA2, releasing the fusion hydrophobic peptide. Several trimers are required to form a competent fusion pore. Publication Abstract from PubMedArrestins have pivotal roles in regulating G protein-coupled receptor (GPCR) signalling by desensitizing G protein activation and mediating receptor internalization(1,2). It has been proposed that the arrestin binds to the receptor in two different conformations, 'tail' and 'core', which were suggested to govern distinct processes of receptor signalling and trafficking(3,4). However, little structural information is available for the tail engagement of the arrestins. Here we report two structures of the glucagon receptor (GCGR) bound to beta-arrestin 1 (betaarr1) in glucagon-bound and ligand-free states. These structures reveal a receptor tail-engaged binding mode of betaarr1 with many unique features, to our knowledge, not previously observed. Helix VIII, instead of the receptor core, has a major role in accommodating betaarr1 by forming extensive interactions with the central crest of betaarr1. The tail-binding pose is further defined by a close proximity between the betaarr1 C-edge and the receptor helical bundle, and stabilized by a phosphoinositide derivative that bridges betaarr1 with helices I and VIII of GCGR. Lacking any contact with the arrestin, the receptor core is in an inactive state and loosely binds to glucagon. Further functional studies suggest that the tail conformation of GCGR-betaarr governs betaarr recruitment at the plasma membrane and endocytosis of GCGR, and provides a molecular basis for the receptor forming a super-complex simultaneously with G protein and betaarr to promote sustained signalling within endosomes. These findings extend our knowledge about the arrestin-mediated modulation of GPCR functionalities. Tail engagement of arrestin at the glucagon receptor.,Chen K, Zhang C, Lin S, Yan X, Cai H, Yi C, Ma L, Chu X, Liu Y, Zhu Y, Han S, Zhao Q, Wu B Nature. 2023 Aug;620(7975):904-910. doi: 10.1038/s41586-023-06420-x. Epub 2023 , Aug 9. PMID:37558880[16] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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