Home LiteratureArticle Details
PMID: 22174878 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

The effect of arrestin conformation on the recruitment of c-Raf1, MEK1, and ERK1/2 activation.

PloS one ·Vol. 6 ·No. 12 ·2011-00-00 ·Pages e28723

Coffa S, Breitman M, Hanson SM, Callaway K, Kook S, Dalby KN, Gurevich VV

Abstract

Arrestins are multifunctional signaling adaptors originally discovered as proteins that "arrest" G protein activation by G protein-coupled receptors (GPCRs). Recently GPCR complexes with arrestins have been proposed to activate G protein-independent signaling pathways. In particular, arrestin-dependent activation of extracellular signal-regulated kinase 1/2 (ERK1/2) has been demonstrated. Here we have performed in vitro binding assays with pure proteins to demonstrate for the first time that ERK2 directly binds free arrestin-2 and -3, as well as receptor-associated arrestins-1, -2, and -3. In addition, we showed that in COS-7 cells arrestin-2 and -3 association with β(2)-adrenergic receptor (β2AR) significantly enhanced ERK2 binding, but showed little effect on arrestin interactions with the upstream kinases c-Raf1 and MEK1. Arrestins exist in three conformational states: free, receptor-bound, and microtubule-associated. Using conformationally biased arrestin mutants we found that ERK2 preferentially binds two of these: the "constitutively inactive" arrestin-Δ7 mimicking microtubule-bound state and arrestin-3A, a mimic of the receptor-bound conformation. Both rescue arrestin-mediated ERK1/2/activation in arrestin-2/3 double knockout fibroblasts. We also found that arrestin-2-c-Raf1 interaction is enhanced by receptor binding, whereas arrestin-3-c-Raf1 interaction is not.

MeSH Terms
Animals Arrestin/chemistry,metabolism Arrestins/chemistry,metabolism COS Cells Cattle Chlorocebus aethiops Embryo, Mammalian/cytology Enzyme Activation Fibroblasts/enzymology HEK293 Cells Humans Ligands MAP Kinase Kinase 1/metabolism Mice Mice, Knockout Mitogen-Activated Protein Kinase 1/metabolism Mitogen-Activated Protein Kinase 3/metabolism Mutant Proteins/chemistry,metabolism Phosphorylation Protein Binding Protein Conformation Proto-Oncogene Proteins c-raf/metabolism Receptors, Adrenergic, beta-2/metabolism Structure-Activity Relationship beta-Arrestins
Chemicals
Arrestin Arrestins Ligands Mutant Proteins Receptors, Adrenergic, beta-2 arrestin3 beta-Arrestins Proto-Oncogene Proteins c-raf Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 MAP Kinase Kinase 1 Map2k1 protein, mouse
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Coffa Sergio
Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, United States of America.
Breitman Maya
Hanson Susan M
Callaway Kari
Kook Seunghyi
Dalby Kevin N
Gurevich Vsevolod V
References (60)
60 references, click to expand
  1. Conformational differences between arrestin2 and pre-activated mutants as revealed by hydrogen exchange mass spectrometry.
    J Mol Biol. 2005 Aug 26;351(4):865-78 PMID: 16045931
  2. New mechanisms in heptahelical receptor signaling to mitogen activated protein kinase cascades.
    Oncogene. 2001 Mar 26;20(13):1532-9 PMID: 11313899
  3. Conservation of the phosphate-sensitive elements in the arrestin family of proteins.
    J Biol Chem. 2002 Mar 15;277(11):9043-8 PMID: 11782458
  4. Crystal structure of beta-arrestin at 1.9 A: possible mechanism of receptor binding and membrane Translocation.
    Structure. 2001 Sep;9(9):869-80 PMID: 11566136
  5. Phosphorylated rhodopsin and heparin induce similar conformational changes in arrestin.
    J Biol Chem. 1991 Oct 5;266(28):18649-54 PMID: 1917988
  6. Differential interaction of spin-labeled arrestin with inactive and active phosphorhodopsin.
    Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):4900-5 PMID: 16547131
  7. The Ste5 scaffold directs mating signaling by catalytically unlocking the Fus3 MAP kinase for activation.
    Cell. 2009 Mar 20;136(6):1085-97 PMID: 19303851
  8. Enhanced arrestin facilitates recovery and protects rods lacking rhodopsin phosphorylation.
    Curr Biol. 2009 Apr 28;19(8):700-5 PMID: 19361994
  9. Targeted construction of phosphorylation-independent beta-arrestin mutants with constitutive activity in cells.
    J Biol Chem. 1999 Mar 12;274(11):6831-4 PMID: 10066734
  10. Structure and function of the visual arrestin oligomer.
    EMBO J. 2007 Mar 21;26(6):1726-36 PMID: 17332750
  11. Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3.
    Science. 2000 Nov 24;290(5496):1574-7 PMID: 11090355
  12. Kappa opioid receptor activation of p38 MAPK is GRK3- and arrestin-dependent in neurons and astrocytes.
    J Biol Chem. 2006 Jun 30;281(26):18081-9 PMID: 16648139
  13. The differential engagement of arrestin surface charges by the various functional forms of the receptor.
    J Biol Chem. 2006 Feb 10;281(6):3458-62 PMID: 16339758
  14. Crystal structure of cone arrestin at 2.3A: evolution of receptor specificity.
    J Mol Biol. 2005 Dec 16;354(5):1069-80 PMID: 16289201
  15. Two rate-limiting steps in the kinetic mechanism of the serine/threonine specific protein kinase ERK2: a case of fast phosphorylation followed by fast product release.
    Biochemistry. 2003 Oct 28;42(42):12273-86 PMID: 14567689
  16. The functional cycle of visual arrestins in photoreceptor cells.
    Prog Retin Eye Res. 2011 Nov;30(6):405-30 PMID: 21824527
  17. beta-Arrestin 1 and 2 differentially regulate heptahelical receptor signaling and trafficking.
    Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1601-6 PMID: 11171997
  18. Topographic study of arrestin using differential chemical modifications and hydrogen/deuterium exchange.
    Protein Sci. 1994 Dec;3(12):2428-34 PMID: 7756996
  19. Few residues within an extensive binding interface drive receptor interaction and determine the specificity of arrestin proteins.
    J Biol Chem. 2011 Jul 8;286(27):24288-99 PMID: 21471193
  20. Each rhodopsin molecule binds its own arrestin.
    Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3125-8 PMID: 17360618
  21. Arrestins: ubiquitous regulators of cellular signaling pathways.
    Genome Biol. 2006;7(9):236 PMID: 17020596
  22. The role of arrestin alpha-helix I in receptor binding.
    J Mol Biol. 2010 Jan 8;395(1):42-54 PMID: 19883657
  23. Mapping the arrestin-receptor interface. Structural elements responsible for receptor specificity of arrestin proteins.
    J Biol Chem. 2004 Jan 9;279(2):1262-8 PMID: 14530255
  24. Interactions of metarhodopsin II. Arrestin peptides compete with arrestin and transducin.
    J Biol Chem. 2000 Dec 1;275(48):37679-85 PMID: 10969086
  25. MEK1 binds directly to betaarrestin1, influencing both its phosphorylation by ERK and the timing of its isoprenaline-stimulated internalization.
    J Biol Chem. 2009 Apr 24;284(17):11425-35 PMID: 19153083
  26. Visual and both non-visual arrestins in their "inactive" conformation bind JNK3 and Mdm2 and relocalize them from the nucleus to the cytoplasm.
    J Biol Chem. 2006 Jul 28;281(30):21491-21499 PMID: 16737965
  27. Beta-arrestin-mediated activation of MAPK by inverse agonists reveals distinct active conformations for G protein-coupled receptors.
    Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11406-11 PMID: 13679574
  28. Nonvisual arrestins function as simple scaffolds assembling the MKK4-JNK3α2 signaling complex.
    Biochemistry. 2011 Dec 6;50(48):10520-9 PMID: 22047447
  29. Crystal structure of the β2 adrenergic receptor-Gs protein complex.
    Nature. 2011 Jul 19;477(7366):549-55 PMID: 21772288
  30. A single mutation in arrestin-2 prevents ERK1/2 activation by reducing c-Raf1 binding.
    Biochemistry. 2011 Aug 16;50(32):6951-8 PMID: 21732673
  31. Arrestin-1 expression level in rods: balancing functional performance and photoreceptor health.
    Neuroscience. 2011 Feb 3;174:37-49 PMID: 21075174
  32. Arrestin interactions with G protein-coupled receptors. Direct binding studies of wild type and mutant arrestins with rhodopsin, beta 2-adrenergic, and m2 muscarinic cholinergic receptors.
    J Biol Chem. 1995 Jan 13;270(2):720-31 PMID: 7822302
  33. Phosphodiesterase activation by photoexcited rhodopsin is quenched when rhodopsin is phosphorylated and binds the intrinsic 48-kDa protein of rod outer segments.
    Proc Natl Acad Sci U S A. 1986 Mar;83(5):1174-8 PMID: 3006038
  34. The nature of the arrestin x receptor complex determines the ultimate fate of the internalized receptor.
    J Biol Chem. 2003 Mar 28;278(13):11623-32 PMID: 12525498
  35. The structural basis of arrestin-mediated regulation of G-protein-coupled receptors.
    Pharmacol Ther. 2006 Jun;110(3):465-502 PMID: 16460808
  36. Visual arrestin binding to microtubules involves a distinct conformational change.
    J Biol Chem. 2006 Apr 7;281(14):9765-72 PMID: 16461350
  37. How does arrestin assemble MAPKs into a signaling complex?
    J Biol Chem. 2009 Jan 2;284(1):685-695 PMID: 19001375
  38. Transition of arrestin into the active receptor-binding state requires an extended interdomain hinge.
    J Biol Chem. 2002 Nov 15;277(46):43961-7 PMID: 12215448
  39. Duration and amplitude of the light-induced cGMP hydrolysis in vertebrate photoreceptors are regulated by multiple phosphorylation of rhodopsin and by arrestin binding.
    Biochemistry. 1995 Jan 31;34(4):1446-54 PMID: 7827093
  40. Insertional mutagenesis and immunochemical analysis of visual arrestin interaction with rhodopsin.
    J Biol Chem. 2002 Apr 5;277(14):11703-8 PMID: 11809770
  41. A mutation-induced activated state of the beta 2-adrenergic receptor. Extending the ternary complex model.
    J Biol Chem. 1993 Mar 5;268(7):4625-36 PMID: 8095262
  42. Kinetics, binding constant, and activation energy of the 48-kDa protein-rhodopsin complex by extra-metarhodopsin II.
    Biochemistry. 1989 Feb 21;28(4):1770-5 PMID: 2719933
  43. Ligand-specific regulation of the extracellular surface of a G-protein-coupled receptor.
    Nature. 2010 Jan 7;463(7277):108-12 PMID: 20054398
  44. Arrestin: mutagenesis, expression, purification, and functional characterization.
    Methods Enzymol. 2000;315:422-37 PMID: 10736718
  45. The selectivity of visual arrestin for light-activated phosphorhodopsin is controlled by multiple nonredundant mechanisms.
    J Biol Chem. 1998 Jun 19;273(25):15501-6 PMID: 9624137
  46. The molecular acrobatics of arrestin activation.
    Trends Pharmacol Sci. 2004 Feb;25(2):105-11 PMID: 15102497
  47. Cone arrestin binding to JNK3 and Mdm2: conformational preference and localization of interaction sites.
    J Neurochem. 2007 Nov;103(3):1053-62 PMID: 17680991
  48. The 2.8 A crystal structure of visual arrestin: a model for arrestin's regulation.
    Cell. 1999 Apr 16;97(2):257-69 PMID: 10219246
  49. ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF.
    Cell. 1991 May 17;65(4):663-75 PMID: 2032290
  50. Crystal structure of arrestin-3 reveals the basis of the difference in receptor binding between two non-visual subtypes.
    J Mol Biol. 2011 Feb 25;406(3):467-78 PMID: 21215759
  51. beta-Arrestin scaffolding of the ERK cascade enhances cytosolic ERK activity but inhibits ERK-mediated transcription following angiotensin AT1a receptor stimulation.
    J Biol Chem. 2002 Mar 15;277(11):9429-36 PMID: 11777902
  52. Regulation of arrestin binding by rhodopsin phosphorylation level.
    J Biol Chem. 2007 Nov 2;282(44):32075-83 PMID: 17848565
  53. Arrestins as multi-functional signaling adaptors.
    Handb Exp Pharmacol. 2008;(186):15-37 PMID: 18491047
  54. Arrestin mobilizes signaling proteins to the cytoskeleton and redirects their activity.
    J Mol Biol. 2007 Apr 27;368(2):375-87 PMID: 17359998
  55. Mechanism of quenching of phototransduction. Binding competition between arrestin and transducin for phosphorhodopsin.
    J Biol Chem. 1997 Jul 18;272(29):18125-31 PMID: 9218446
  56. Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds.
    Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2449-54 PMID: 11226259
  57. Ubiquitin ligase parkin promotes Mdm2-arrestin interaction but inhibits arrestin ubiquitination.
    Biochemistry. 2011 May 10;50(18):3749-63 PMID: 21466165
  58. M3 muscarinic acetylcholine receptor-mediated signaling is regulated by distinct mechanisms.
    Mol Pharmacol. 2008 Aug;74(2):338-47 PMID: 18388243
  59. Agonist-receptor-arrestin, an alternative ternary complex with high agonist affinity.
    J Biol Chem. 1997 Nov 14;272(46):28849-52 PMID: 9360951
  60. Reciprocal regulation of angiotensin receptor-activated extracellular signal-regulated kinases by beta-arrestins 1 and 2.
    J Biol Chem. 2004 Feb 27;279(9):7807-11 PMID: 14711824
Article Info
Journal
PloS one
Abbr.
PLoS One
ISSN
1932-6203
DOI
10.1371/journal.pone.0028723
Published
2011-00-00
Epub
2011-00-12
Pages
e28723
Language
English
Region
United States
NLM ID
101285081
PMCID
PMC3236217
Subset
IM
Grants
NIGMS NIH HHS · GM059802 · United States
NIGMS NIH HHS · R01 GM059802 · United States
NIGMS NIH HHS · GM081756 · United States
NIGMS NIH HHS · R01 GM077561 · United States
NEI NIH HHS · EY011500 · United States
NIGMS NIH HHS · GM077561 · United States
NEI NIH HHS · R01 EY011500 · United States
PHS HHS · F-1390 · United States
NIGMS NIH HHS · R01 GM081756 · United States
External Links
PubMed source DOI: 10.1371/journal.pone.0028723 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2