6tko
From Proteopedia
Phosphorylated turkey beta1 adrenoceptor with bound agonist formoterol coupled to arrestin-2 in lipid nanodisc.
Structural highlights
Function[ADRB1_MELGA] Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins. This receptor binds epinephrine and norepinephrine with approximately equal affinity. [ARRB1_HUMAN] Functions in regulating agonist-mediated G-protein coupled receptor (GPCR) signaling by mediating both receptor desensitization and resensitization processes. During homologous desensitization, beta-arrestins bind to the GPRK-phosphorylated receptor and sterically preclude its coupling to the cognate G-protein; the binding appears to require additional receptor determinants exposed only in the active receptor conformation. The beta-arrestins target many receptors for internalization by acting as endocytic adapters (CLASPs, clathrin-associated sorting proteins) and recruiting the GPRCs to the adapter protein 2 complex 2 (AP-2) in clathrin-coated pits (CCPs). However, the extent of beta-arrestin involvement appears to vary significantly depending on the receptor, agonist and cell type. Internalized arrestin-receptor complexes traffic to intracellular endosomes, where they remain uncoupled from G-proteins. Two different modes of arrestin-mediated internalization occur. Class A receptors, like ADRB2, OPRM1, ENDRA, D1AR and ADRA1B dissociate from beta-arrestin at or near the plasma membrane and undergo rapid recycling. Class B receptors, like AVPR2, AGTR1, NTSR1, TRHR and TACR1 internalize as a complex with arrestin and traffic with it to endosomal vesicles, presumably as desensitized receptors, for extended periods of time. Receptor resensitization then requires that receptor-bound arrestin is removed so that the receptor can be dephosphorylated and returned to the plasma membrane. Involved in internalization of P2RY4 and UTP-stimulated internalization of P2RY2. Involved in phosphorylation-dependent internalization of OPRD1 ands subsequent recycling. Involved in the degradation of cAMP by recruiting cAMP phosphodiesterases to ligand-activated receptors. Beta-arrestins function as multivalent adapter proteins that can switch the GPCR from a G-protein signaling mode that transmits short-lived signals from the plasma membrane via small molecule second messengers and ion channels to a beta-arrestin signaling mode that transmits a distinct set of signals that are initiated as the receptor internalizes and transits the intracellular compartment. Acts as signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2). ERK1/2 activated by the beta-arrestin scaffold is largely excluded from the nucleus and confined to cytoplasmic locations such as endocytic vesicles, also called beta-arrestin signalosomes. Recruits c-Src/SRC to ADRB2 resulting in ERK activation. GPCRs for which the beta-arrestin-mediated signaling relies on both ARRB1 and ARRB2 (codependent regulation) include ADRB2, F2RL1 and PTH1R. For some GPCRs the beta-arrestin-mediated signaling relies on either ARRB1 or ARRB2 and is inhibited by the other respective beta-arrestin form (reciprocal regulation). Inhibits ERK1/2 signaling in AGTR1- and AVPR2-mediated activation (reciprocal regulation). Is required for SP-stimulated endocytosis of NK1R and recruits c-Src/SRC to internalized NK1R resulting in ERK1/2 activation, which is required for the antiapoptotic effects of SP. Is involved in proteinase-activated F2RL1-mediated ERK activity. Acts as signaling scaffold for the AKT1 pathway. Is involved in alpha-thrombin-stimulated AKT1 signaling. Is involved in IGF1-stimulated AKT1 signaling leading to increased protection from apoptosis. Involved in activation of the p38 MAPK signaling pathway and in actin bundle formation. Involved in F2RL1-mediated cytoskeletal rearrangement and chemotaxis. Involved in AGTR1-mediated stress fiber formation by acting together with GNAQ to activate RHOA. Appears to function as signaling scaffold involved in regulation of MIP-1-beta-stimulated CCR5-dependent chemotaxis. Involved in attenuation of NF-kappa-B-dependent transcription in response to GPCR or cytokine stimulation by interacting with and stabilizing CHUK. May serve as nuclear messenger for GPCRs. Involved in OPRD1-stimulated transcriptional regulation by translocating to CDKN1B and FOS promoter regions and recruiting EP300 resulting in acetylation of histone H4. Involved in regulation of LEF1 transcriptional activity via interaction with DVL1 and/or DVL2 Also involved in regulation of receptors other than GPCRs. Involved in Toll-like receptor and IL-1 receptor signaling through the interaction with TRAF6 which prevents TRAF6 autoubiquitination and oligomerization required for activation of NF-kappa-B and JUN. Binds phosphoinositides. Binds inositolhexakisphosphate (InsP6) (By similarity). Involved in IL8-mediated granule release in neutrophils.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] Publication Abstract from PubMedThe beta1-adrenoceptor (beta1AR) is a G-protein-coupled receptor (GPCR) that couples(1) to the heterotrimeric G protein Gs. G-protein-mediated signalling is terminated by phosphorylation of the C terminus of the receptor by GPCR kinases (GRKs) and by coupling of beta-arrestin 1 (betaarr1, also known as arrestin 2), which displaces Gs and induces signalling through the MAP kinase pathway(2). The ability of synthetic agonists to induce signalling preferentially through either G proteins or arrestins-known as biased agonism(3)-is important in drug development, because the therapeutic effect may arise from only one signalling cascade, whereas the other pathway may mediate undesirable side effects(4). To understand the molecular basis for arrestin coupling, here we determined the cryo-electron microscopy structure of the beta1AR-betaarr1 complex in lipid nanodiscs bound to the biased agonist formoterol(5), and the crystal structure of formoterol-bound beta1AR coupled to the G-protein-mimetic nanobody(6) Nb80. betaarr1 couples to beta1AR in a manner distinct to that(7) of Gs coupling to beta2AR-the finger loop of betaarr1 occupies a narrower cleft on the intracellular surface, and is closer to transmembrane helix H7 of the receptor when compared with the C-terminal alpha5 helix of Gs. The conformation of the finger loop in betaarr1 is different from that adopted by the finger loop of visual arrestin when it couples to rhodopsin(8). beta1AR coupled to betaarr1 shows considerable differences in structure compared with beta1AR coupled to Nb80, including an inward movement of extracellular loop 3 and the cytoplasmic ends of H5 and H6. We observe weakened interactions between formoterol and two serine residues in H5 at the orthosteric binding site of beta1AR, and find that formoterol has a lower affinity for the beta1AR-betaarr1 complex than for the beta1AR-Gs complex. The structural differences between these complexes of beta1AR provide a foundation for the design of small molecules that could bias signalling in the beta-adrenoceptors. Molecular basis of beta-arrestin coupling to formoterol-bound beta1-adrenoceptor.,Lee Y, Warne T, Nehme R, Pandey S, Dwivedi-Agnihotri H, Chaturvedi M, Edwards PC, Garcia-Nafria J, Leslie AGW, Shukla AK, Tate CG Nature. 2020 Jun 17. pii: 10.1038/s41586-020-2419-1. doi:, 10.1038/s41586-020-2419-1. PMID:32555462[17] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Human | Large Structures | Melga | Phage display vector ptdisp | Lee, Y | Tate, C G | Arrestin | Complex | Gpcr | Nanodisc | Signaling protein
