Arrestins: Discovery of the Family and Functional Role of Conformational Flexibility

  • Vsevolod V. GurevichEmail author
  • Eugenia V. GurevichEmail author


Arrestins were first discovered as negative regulators of G protein-mediated signaling by GPCRs: they bind GRK-phosphorylated active receptors and preclude their further coupling to cognate G proteins. Vertebrates have only four arrestin subtypes, two of which are specifically expressed in photoreceptors in the retina, whereas the two non-visual arrestins are ubiquitously expressed and apparently regulate hundreds of different GPCRs. Later studies showed that, in addition to receptors, non-visual arrestins interact with dozens of other signaling proteins. Current view is that arrestins are versatile regulators organizing multi-protein signaling complexes and localizing them to particular subcellular compartments. Arrestins can exist in several distinct conformations, the best-studied being basal and receptor-bound (often termed “active”), which differentially engage various partners. Identification of the arrestin elements engaged by each partner and construction of signaling-biased arrestins where individual functions are selectively disrupted or enhanced, helps us to elucidate their biological roles in the cell.


Arrestin GPCR Desensitization Signaling proteins Scaffolding Protein conformation 



Supported by NIH Grants EY011500, GM077561, GM109955 (VVG), NS065868, and DA030103 (EVG).


  1. Ahmed MR, Zhan X, Song X, Kook S, Gurevich VV, Gurevich EV (2011) Ubiquitin ligase parkin promotes Mdm2-arrestin interaction but inhibits arrestin ubiquitination. Biochemistry 50:3749–3763Google Scholar
  2. Attramadal H, Arriza JL, Aoki C, Dawson TM, Codina J, Kwatra MM, Snyder SH, Caron MG, Lefkowitz RJ (1992) Beta-arrestin2, a novel member of the arrestin/beta-arrestin gene family. J Biol Chem 267:17882–17890PubMedGoogle Scholar
  3. Barak LS, Ferguson SS, Zhang J, Caron MG (1997) A beta-arrestin/green fluorescent protein biosensor for detecting G protein-coupled receptor activation. J Biol Chem 272:27497–27500PubMedCrossRefGoogle Scholar
  4. Benovic JL, Kühn H, Weyand I, Codina J, Caron MG, Lefkowitz RJ (1987) Functional desensitization of the isolated β-adrenergic receptor by the β-adrenergic receptor kinase: potential role of an analog of the retinal protein arrestin (48 kDa protein). Proc Natl Acad Sci 84:8879–8882PubMedPubMedCentralCrossRefGoogle Scholar
  5. Benovic JL, DeBlasi A, Stone WC, Caron MG, Lefkowitz RJ (1989) Beta-adrenergic receptor kinase: primary structure delineates a multigene family. Science 246:235–240PubMedCrossRefGoogle Scholar
  6. Bhandari D, Trejo J, Benovic JL, Marchese A (2007) Arrestin-2 interacts with the ubiquitin-protein isopeptide ligase atrophin-interacting protein 4 and mediates endosomal sorting of the chemokine receptor CXCR4. J Biol Chem 282:36971–36979PubMedCrossRefGoogle Scholar
  7. Breitman M, Kook S, Gimenez LE, Lizama BN, Palazzo MC, Gurevich EV, Gurevich VV (2012) Silent scaffolds: inhibition of c-Jun N-terminal kinase 3 activity in the cell by a dominant-negative arrestin-3 mutant. J Biol Chem 287:19653–19664PubMedPubMedCentralCrossRefGoogle Scholar
  8. Bruchas MR, Macey TA, Lowe JD, Chavkin C (2006) Kappa opioid receptor activation of p38 MAPK is GRK3- and arrestin-dependent in neurons and astrocytes. J Biol Chem 281:18081–18089PubMedPubMedCentralCrossRefGoogle Scholar
  9. Celver J, Lowe J, Kovoor A, Gurevich VV, Chavkin C (2001) Threonine 180 is required for G protein-coupled receptor kinase 3 and b-arrestin mediated desensitization of the m-opioid receptor in Xenopus oocytes. J Biol Chem 276:4894–4900PubMedCrossRefGoogle Scholar
  10. Celver J, Vishnivetskiy SA, Chavkin C, Gurevich VV (2002) Conservation of the phosphate-sensitive elements in the arrestin family of proteins. J Biol Chem 277:9043–9048PubMedCrossRefGoogle Scholar
  11. Chan S, Rubin WW, Mendez A, Liu X, Song X, Hanson SM, Craft CM, Gurevich VV, Burns ME, Chen J (2007) Functional comparisons of visual arrestins in rod photoreceptors of transgenic mice. Invest Ophthalmol Vis Sci 48:1968–1975PubMedPubMedCentralCrossRefGoogle Scholar
  12. Coffa S, Breitman M, Hanson SM, Callaway K, Kook S, Dalby KN, Gurevich VV (2011) The effect of arrestin conformation on the recruitment of c-Raf1, MEK1, and ERK1/2 activation. PLoS ONE 6:e28723PubMedPubMedCentralCrossRefGoogle Scholar
  13. Craft CM, Whitmore DH, Wiechmann AF (1994) Cone arrestin identified by targeting expression of a functional family. J Biol Chem 269:4613–4619PubMedGoogle Scholar
  14. DeFea KA, Vaughn ZD, O’Bryan EM, Nishijima D, Déry O, Bunnett NW (2000a) The proliferative and antiapoptotic effects of substance P are facilitated by formation of a beta-arrestin-dependent scaffolding complex. Proc Natl Acad Sci USA 97:11086–11091PubMedPubMedCentralCrossRefGoogle Scholar
  15. DeFea KA, Zalevsky J, Thoma MS, Déry O, Mullins RD, Bunnett NW (2000b) Beta-arrestin-dependent endocytosis of proteinase-activated receptor 2 is required for intracellular targeting of activated ERK1/2. J Cell Biol 148:1267–1281PubMedPubMedCentralCrossRefGoogle Scholar
  16. DeWire SM, Ahn S, Lefkowitz RJ, Shenoy SK (2007) Beta-arrestins and cell signaling. Ann Rev Physiol 69:483–510CrossRefGoogle Scholar
  17. Dixon RA, Kobilka BK, Strader DJ, Benovic JL, Dohlman HG, Frielle T, Bolanowski MA, Bennett CD, Rands E, Diehl RE, Mumford RA, Slater EE, Sigal IS, Caron MG, Lefkowitz RJ, Strader CD (1986) Cloning of the gene and cDNA for mammalian beta-adrenergic receptor and homology with rhodopsin. Nature 321:75–79PubMedCrossRefGoogle Scholar
  18. Farrens DL, Altenbach C, Yang K, Hubbell WL, Khorana HG (1996) Requirement of rigid-body motion of transmembrane helices for light activation of rhodopsin. Science 274:768–770PubMedCrossRefGoogle Scholar
  19. Goodman OB Jr, Krupnick JG, Santini F, Gurevich VV, Penn RB, Gagnon AW, Keen JH, Benovic JL (1996) Beta-arrestin acts as a clathrin adaptor in endocytosis of the beta2-adrenergic receptor. Nature 383:447–450PubMedCrossRefGoogle Scholar
  20. Granzin J, Wilden U, Choe HW, Labahn J, Krafft B, Buldt G (1998) X-ray crystal structure of arrestin from bovine rod outer segments. Nature 391:918–921PubMedCrossRefGoogle Scholar
  21. Granzin J, Cousin A, Weirauch M, Schlesinger R, Büldt G, Batra-Safferling R (2012) Crystal structure of p44, a constitutively active splice variant of visual arrestin. J Mol Biol 416:611–618PubMedCrossRefGoogle Scholar
  22. Gray-Keller MP, Detwiler PB, Benovic JL, Gurevich VV (1997) Arrestin with a single amino acid substitution quenches light-activated rhodopsin in a phosphorylation-independent fasion. Biochemistry 36:7058–7063PubMedCrossRefGoogle Scholar
  23. Gurevich VV, Benovic JL (1993) Visual arrestin interaction with rhodopsin: sequential multisite binding ensures strict selectivity towards light-activated phosphorylated rhodopsin. J Biol Chem 268:11628–11638PubMedGoogle Scholar
  24. Gurevich VV, Benovic JL (1995) Visual arrestin binding to rhodopsin: diverse functional roles of positively charged residues within the phosphorylation-recognition region of arrestin. J Biol Chem 270:6010–6016PubMedCrossRefGoogle Scholar
  25. Gurevich VV, Benovic JL (1997) Mechanism of phosphorylation-recognition by visual arrestin and the transition of arrestin into a high affinity binding state. Mol Pharmacol 51:161–169PubMedGoogle Scholar
  26. Gurevich VV, Gurevich EV (2003) The new face of active receptor bound arrestin attracts new partners. Structure 11:1037–1042PubMedCrossRefGoogle Scholar
  27. Gurevich VV, Gurevich EV (2004) The molecular acrobatics of arrestin activation. Trends Pharmacol Sci 25:105–111PubMedCrossRefGoogle Scholar
  28. Gurevich VV, Gurevich EV (2006a) The structural basis of arrestin-mediated regulation of G protein-coupled receptors. Pharm Ther 110:465–502CrossRefGoogle Scholar
  29. Gurevich EV, Gurevich VV (2006b) Arrestins are ubiquitous regulators of cellular signaling pathways. Genome Biol 7:236PubMedPubMedCentralCrossRefGoogle Scholar
  30. Gurevich VV, Gurevich EV (2014) Extensive shape shifting underlies functional versatility of arrestins. Curr Opin Cell Biol 27:1–9PubMedCrossRefGoogle Scholar
  31. Gurevich VV, Richardson RM, Kim CM, Hosey MM, Benovic JL (1993) Binding of wild type and chimeric arrestins to the m2 muscarinic cholinergic receptor. J Biol Chem 268:16879–16882PubMedGoogle Scholar
  32. Gurevich VV, Chen C-Y, Kim CM, Benovic JL (1994) Visual arrestin binding to rhodopsin: intramolecular interaction between the basic N-terminus and acidic C-terminus of arrestin may regulate binding selectivity. J Biol Chem 269:8721–8727PubMedGoogle Scholar
  33. Gurevich VV, Dion SB, Onorato JJ, Ptasienski J, Kim CM, Sterne-Marr R, Hosey MM, Benovic JL (1995) Arrestin interaction with G protein-coupled receptors. Direct binding studies of wild type and mutant arrestins with rhodopsin, b2-adrenergic, and m2 muscarinic cholinergic receptors. J Biol Chem 270:720–731PubMedCrossRefGoogle Scholar
  34. Han M, Gurevich VV, Vishnivetskiy SA, Sigler PB, Schubert C (2001) Crystal structure of beta-arrestin at 1.9 Å: possible mechanism of receptor binding and membrane translocation. Structure 9:869–880PubMedCrossRefGoogle Scholar
  35. Hanson SM, Francis DJ, Vishnivetskiy SA, Klug CS, Gurevich VV (2006a) Visual arrestin binding to microtubules involves a distinct conformational change. J Biol Chem 281:9765–9772PubMedPubMedCentralCrossRefGoogle Scholar
  36. Hanson SM, Francis DJ, Vishnivetskiy SA, Kolobova EA, Hubbell WL, Klug CS, Gurevich VV (2006b) Differential interaction of spin-labeled arrestin with inactive and active phosphorhodopsin. Proc Natl Acad Sci USA 103:4900–4905PubMedPubMedCentralCrossRefGoogle Scholar
  37. Hanson SM, Cleghorn WM, Francis DJ, Vishnivetskiy SA, Raman D, Song X, Nair KS, Slepak VZ, Klug CS, Gurevich VV (2007) Arrestin mobilizes signaling proteins to the cytoskeleton and redirects their activity. J Mol Biol (in press)Google Scholar
  38. Hirsch JA, Schubert C, Gurevich VV, Sigler PB (1999) The 2.8 Å crystal structure of visual arrestin: a model for arrestin’s regulation. Cell 97:257–269PubMedCrossRefGoogle Scholar
  39. Huang SP, Brown BM, Craft CM (2010) Visual arrestin 1 acts as a modulator for N-ethylmaleimide-sensitive factor in the photoreceptor synapse. J Neurosci 30:9381–9391PubMedPubMedCentralCrossRefGoogle Scholar
  40. Huppertz B, Weyand I, Bauer PJ (1990) Ca2+ binding capacity of cytoplasmic proteins from rod photoreceptors is mainly due to arrestin. J Biol Chem 265:9470–9475PubMedGoogle Scholar
  41. Kang Y, Zhou XE, Gao X, He Y, Liu W, Ishchenko A, Barty A, White TA, Yefanov O, Han GW, Xu Q, de Waal PW, Ke J, Tan MHE, Zhang C, Moeller A, West GM, Van Eps N, Caro LN, Vishnivetskiy SA, Lee RJ, Suino-Powell KM, Gu X, Pal K, Ma J, Zhi X, Boutet S, Williams GJ, Messerschmidt M, Gati C, Zatsepin NA, Wang D, James D, Basu S, Roy-Chowdhuty S, Conrad S, Coe J, Liu H, Lisova S, Kupitz C, Grotjohann I, Fromme R, Jiang Y, Tan M, Yang H, Li J, Wang M, Zheng Z, Li D, Zhao Y, Standfuss J, Diederichs K, Dong Y, Potter CS, Carragher B, Caffrey M, Jiang H, Chapman HN, Spence JCH, Fromme P, Weierstall U, Ernst OP, Katritch V, Gurevich VV, Griffin PR, Hubbell WL, Stevens RC, Cherezov V, Melcher K, Xu HE (2015) Crystal structure of rhodopsin bound to arrestin determined by femtosecond X-ray laser. Nature 523:561–567PubMedPubMedCentralCrossRefGoogle Scholar
  42. Kim YM, Benovic JL (2002) Differential roles of arrestin-2 interaction with clathrin and adaptor protein 2 in G protein-coupled receptor trafficking. J Biol Chem 277:30760–30768PubMedCrossRefGoogle Scholar
  43. Kim M, Vishnivetskiy SA, Van Eps N, Alexander NS, Cleghorn WM, Zhan X, Hanson SM, Morizumi T, Ernst OP, Meiler J, Gurevich VV, Hubbell WL (2012) Conformation of receptor-bound visual arrestin. Proc Nat Acad Sci USA 109:18407–18412PubMedPubMedCentralCrossRefGoogle Scholar
  44. Kim YJ, Hofmann KP, Ernst OP, Scheerer P, Choe HW, Sommer ME (2013) Crystal structure of pre-activated arrestin p44. Nature 497:142–146PubMedCrossRefGoogle Scholar
  45. Kook S, Zhan X, Kaoud TS, Dalby KN, Gurevich VV, Gurevich EV (2014) Arrestin-3 binds c-Jun N-terminal kinase 1 (JNK1) and JNK2 and facilitates the activation of these ubiquitous JNK isoforms in cells via scaffolding. J Biol Chem 288:37332–37342Google Scholar
  46. Kovoor A, Celver J, Abdryashitov RI, Chavkin C, Gurevich VV (1999) Targeted construction of phosphorylation-independent β-arrestin mutants with constitutive activity in cells. J Biol Chem 274:6831–6834PubMedCrossRefGoogle Scholar
  47. Krupnick JG, Gurevich VV, Benovic JL (1997a) Mechanism of quenching of phototransduction. Binding competition between arrestin and transducin for phosphorhodopsin. J Biol Chem 272:18125–18131PubMedCrossRefGoogle Scholar
  48. Krupnick JG, Santini F, Gagnon AW, Keen JH, Benovic JL (1997b) Modulation of the arrestin-clathrin interaction in cells. Characterization of beta-arrestin dominant-negative mutants. J Biol Chem 272:32507–32512PubMedCrossRefGoogle Scholar
  49. Kuhn H (1978) Light-regulated binding of rhodopsin kinase and other proteins to cattle photoreceptor membranes. Biochemistry 17:4389–4395PubMedCrossRefGoogle Scholar
  50. Kuhn H, Hall SW, Wilden U (1984) Light-induced binding of 48-kDa protein to photoreceptor membranes is highly enhanced by phosphorylation of rhodopsin. FEBS Lett 176:473–478PubMedCrossRefGoogle Scholar
  51. Laporte SA, Oakley RH, Zhang J, Holt JA, Ferguson SSG, Caron MG, Barak LS (1999) The 2-adrenergic receptor/arrestin complex recruits the clathrin adaptor AP-2 during endocytosis. Proc Nat Acad Sci USA 96:3712–3717PubMedPubMedCentralCrossRefGoogle Scholar
  52. Lau EK, Trester-Zedlitz M, Trinidad JC, Kotowski SJ, Krutchinsky AN, Burlingame AL, von Zastrow M (2011) Quantitative encoding of the effect of a partial agonist on individual opioid receptors by multisite phosphorylation and threshold detection. Sci Signal 4:ra52PubMedPubMedCentralGoogle Scholar
  53. Lee MH, Appleton KM, Strungs EG, Kwon JY, Morinelli TA, Peterson YK, Laporte SA, Luttrell LM (2016) The conformational signature of β-arrestin2 predicts its trafficking and signalling functions. Nature 531:665–668PubMedPubMedCentralCrossRefGoogle Scholar
  54. Lohse MJ, Benovic JL, Codina J, Caron MG, Lefkowitz RJ (1990) Beta-arrestin: a protein that regulates beta-adrenergic receptor function. Science 248:1547–1550PubMedCrossRefGoogle Scholar
  55. Lorenz W, Inglese J, Palczewski K, Onorato JJ, Caron MG, Lefkowitz RJ (1991) The receptor kinase family: primary structure of rhodopsin kinase reveals similarities to the beta-adrenergic receptor kinase. Proc Natl Acad Sci USA 88:8715–8719PubMedPubMedCentralCrossRefGoogle Scholar
  56. Lohse MJ, Andexinger S, Pitcher J, Trukawinski S, Codina J, Faure JP, Caron MG, Lefkowitz RJ (1992) Receptor-specific desensitization with purified proteins. Kinase dependence and receptor specificity of beta-arrestin and arrestin in the beta 2-adrenergic receptor and rhodopsin systems. J Biol Chem 267:8558–8564PubMedGoogle Scholar
  57. Luttrell LM, Ferguson SS, Daaka Y, Miller WE, Maudsley S, Della Rocca GJ, Lin F, Kawakatsu H, Owada K, Luttrell DK, Caron MG, Lefkowitz RJ (1999) Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein kinase complexes. Science 283:655–661PubMedCrossRefGoogle Scholar
  58. Luttrell LM, Roudabush FL, Choy EW, Miller WE, Field ME, Pierce KL, Lefkowitz RJ (2001) Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds. Proc Natl Acad Sci USA 98:2449–2454PubMedPubMedCentralCrossRefGoogle Scholar
  59. McDonald PH, Chow CW, Miller WE, Laporte SA, Field ME, Lin FT, Davis RJ, Lefkowitz RJ (2000) Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3. Science 290:1574–1577PubMedCrossRefGoogle Scholar
  60. Milano SK, Pace HC, Kim YM, Brenner C, Benovic JL (2002) Scaffolding functions of arrestin-2 revealed by crystal structure and mutagenesis. Biochemistry 41:3321–3328PubMedCrossRefGoogle Scholar
  61. Miller WE, McDonald PH, Cai SF, Field ME, Davis RJ, Lefkowitz RJ (2001) Identification of a motif in the carboxyl terminus of beta-arrestin2 responsible for activation of JNK3. J Biol Chem 276:27770–27777PubMedCrossRefGoogle Scholar
  62. Moaven H, Koike Y, Jao CC, Gurevich VV, Langen R, Chen J (2013) Visual arrestin interaction with clathrin adaptor AP-2 regulates photoreceptor survival in the vertebrate retina. Proc Natl Acad Sci USA 110:9463–9468PubMedPubMedCentralCrossRefGoogle Scholar
  63. Modzelewska A, Filipek S, Palczewski K, Park PS (2006) Arrestin interaction with rhodopsin: conceptual models. Cell Biochem Biophys 46:1–15PubMedCrossRefGoogle Scholar
  64. Murakami A, Yajima T, Sakuma H, McLaren MJ, Inana G (1993) X-arrestin: a new retinal arrestin mapping to the X chromosome. FEBS Lett 334:203–209PubMedCrossRefGoogle Scholar
  65. Nikonov SS, Brown BM, Davis JA, Zuniga FI, Bragin A, Pugh EN Jr, Craft CM (2008) Mouse cones require an arrestin for normal inactivation of phototransduction. Neuron 59:462–474PubMedPubMedCentralCrossRefGoogle Scholar
  66. Nobles KN, Xiao K, Ahn S, Shukla AK, Lam CM, Rajagopal S, Strachan RT, Huang TY, Bressler EA, Hara MR, Shenoy SK, Gygi SP, Lefkowitz RJ (2011) Distinct phosphorylation sites on the Œ ≤ (2)-adrenergic receptor establish a barcode that encodes differential functions of Œ ≤ -arrestin. Sci Signal 4:ra51PubMedPubMedCentralCrossRefGoogle Scholar
  67. Noel JP, Hamm HE, Sigler PB (1993) The 2.2 a crystal structure of transducin-alpha complexed with GTP gamma S. Nature 366:654–663PubMedCrossRefGoogle Scholar
  68. Nuber S, Zabel U, Lorenz K, Nuber A, Milligan G, Tobin AB, Lohse MJ, Hoffmann C (2016) β-Arrestin biosensors reveal a rapid, receptor-dependent activation/deactivation cycle. Nature 531:661–664PubMedPubMedCentralCrossRefGoogle Scholar
  69. Orsini MJ, Benovic JL (1998) Characterization of dominant negative arrestins that inhibit beta2-adrenergic receptor internalization by distinct mechanisms. J Biol Chem 273:34616–34622PubMedCrossRefGoogle Scholar
  70. Ovchinnikov YA (1982) Rhodopsin and bacteriorhodopsin: structure-function relationship. FEBS Lett 148:179–191PubMedCrossRefGoogle Scholar
  71. Palczewski K, Hargrave PA (1991) Studies of ligand binding to arrestin. J Biol Chem 266:4201–4206PubMedGoogle Scholar
  72. Palczewski K, Pulvermuller A, Buczylko J, Hofmann KP (1991a) Phosphorylated rhodopsin and heparin induce similar conformational changes in arrestin. J Biol Chem 266:18649–18654PubMedGoogle Scholar
  73. Palczewski K, Buczyłko J, Imami NR, McDowell JH, Hargrave PA (1991b) Role of the carboxyl-terminal region of arrestin in binding to phosphorylated rhodopsin. J Biol Chem 266:15334–15339PubMedGoogle Scholar
  74. Pfister C, Dorey C, Vadot E, Mirshahi M, Deterre P, Chabre M, Faure JP (1984) Identification of the so-called 48 K protein that interacts with illuminated rhodopsin in retinal rods, and the retinal S antigen, inductor of experimental autoimmune uveoretinitis. C R Acad Sci III 299:261–265PubMedGoogle Scholar
  75. Pfister C, Chabre M, Plouet J, Tuyen VV, De Kozak Y, Faure JP, Kühn H (1985) Retinal S antigen identified as the 48 K protein regulating light-dependent phosphodiesterase in rods. Science 228:891–893PubMedCrossRefGoogle Scholar
  76. Rapoport B, Kaufman KD, Chazenbalk GD (1992) Cloning of a member of the arrestin family from a human thyroid cDNA library. Mol Cell Endocrinol 84:R39–R43PubMedCrossRefGoogle Scholar
  77. Rasmussen SG, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VR, Sanishvili R, Fischetti RF, Schertler GF, Weis WI, Kobilka BK (2007) Crystal structure of the human beta2 adrenergic G-protein-coupled receptor. Nature 450:383–387PubMedCrossRefGoogle Scholar
  78. Schleicher A, Kuhn H, Hofmann KP (1989) Kinetics, binding constant, and activation energy of the 48-kDa protein-rhodopsin complex by extra-metarhodopsin II. Biochemistry 28:1770–1775PubMedCrossRefGoogle Scholar
  79. Seo J, Tsakem EL, Breitman M, Gurevich VV (2011) Identification of arrestin-3-specific residues necessary for JNK3 activation. J Biol Chem 286:27894–27901PubMedPubMedCentralCrossRefGoogle Scholar
  80. Shenoy SK, McDonald PH, Kohout TA, Lefkowitz RJ (2001) Regulation of receptor fate by ubiquitination of activated beta 2-adrenergic receptor and beta-arrestin. Science 294:1307–1313PubMedCrossRefGoogle Scholar
  81. Shenoy SK, Modi AS, Shukla AK, Xiao K, Berthouze M, Ahn S, Wilkinson KD, Miller WE, Lefkowitz RJ (2009) Beta-arrestin-dependent signaling and trafficking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2. Proc Nat Acad Sci USA 106:6650–6655PubMedPubMedCentralCrossRefGoogle Scholar
  82. Shichi H, Somers RL (1978) Light-dependent phosphorylation of rhodopsin. Purification and properties of rhodopsin kinase. J Biol Chem 253:7040–7046PubMedGoogle Scholar
  83. Shinohara T, Dietzschold B, Craft CM, Wistow G, Early JJ, Donoso LA, Horwitz J, Tao R (1987) Primary and secondary structure of bovine retinal S antigen (48 kDa protein). Proc Natl Acad Sci 84:6975–6979PubMedPubMedCentralCrossRefGoogle Scholar
  84. Shukla AK, Manglik A, Kruse AC, Xiao K, Reis RI, Tseng WC, Staus DP, Hilger D, Uysal S, Huang LY, Paduch M, Tripathi-Shukla P, Koide A, Koide S, Weis WI, Kossiakoff AA, Kobilka BK, Lefkowitz RJ (2013) Structure of active beta-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide. Nature 497:137–141PubMedPubMedCentralCrossRefGoogle Scholar
  85. Sondek J, Lambright DG, Noel JP, Hamm HE, Sigler PB (1994) GTPase mechanism of Gproteins from the 1.7-A crystal structure of transducin alpha-GDP-AIF-4. Nature 372:276–279PubMedCrossRefGoogle Scholar
  86. Song X, Raman D, Gurevich EV, Vishnivetskiy SA, Gurevich VV (2006) 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 281:21491–21499PubMedPubMedCentralCrossRefGoogle Scholar
  87. Song X, Gurevich EV, Gurevich VV (2007) Cone arrestin binding to JNK3 and Mdm2: conformational preference and localization of interaction sites. J Neurochem 103:1053–1062PubMedPubMedCentralCrossRefGoogle Scholar
  88. Song X, Vishnivetskiy SA, Gross OP, Emelianoff K, Mendez A, Chen J, Gurevich EV, Burns ME, Gurevich VV (2009a) Enhanced arrestin facilitates recovery and protects rods lacking rhodopsin phosphorylation. Curr Biol 19:700–705PubMedPubMedCentralCrossRefGoogle Scholar
  89. Song X, Coffa S, Fu H, Gurevich VV (2009b) How does arrestin assemble MAP kinases into a signaling complex? J Biol Chem 284:685–695PubMedPubMedCentralCrossRefGoogle Scholar
  90. Sterne-Marr R, Gurevich VV, Goldsmith P, Bodine RC, Sanders C, Donoso LA, Benovic JL (1993) Polypeptide variants of beta-arrestin and arrestin3. J Biol Chem 268:15640–15648PubMedGoogle Scholar
  91. Sutton RB, Vishnivetskiy SA, Robert J, Hanson SM, Raman D, Knox BE, Kono M, Navarro J, Gurevich VV (2005) Crystal structure of cone arrestin at 2.3 Å: evolution of receptor specificity. J Mol Biol 354:1069–1080PubMedCrossRefGoogle Scholar
  92. Szczepek M, Beyriere F, Hofmann KP, Elgeti M, Kazmin R, Rose A, Bartl FJ, von Stetten D, Heck M, Sommer ME, Hildebrand PW, Scheerer P (2014) Crystal structure of a common GPCR-binding interface for G protein and arrestin. Nat Commun 5:4801PubMedPubMedCentralCrossRefGoogle Scholar
  93. Tobin AB, Butcher AJ, Kong KC (2008) Location, location, location…site-specific GPCR phosphorylation offers a mechanism for cell-type-specific signalling. Trends Pharmacol Sci 29:413–420PubMedPubMedCentralCrossRefGoogle Scholar
  94. Tsuda M, Syed M, Bugra K, Whelan JP, McGinnis JF, Shinohara T (1988) Structural analysis of mouse S-antigen. Gene 73:11–20PubMedCrossRefGoogle Scholar
  95. Vishnivetskiy SA, Paz CL, Schubert C, Hirsch JA, Sigler PB, Gurevich VV (1999) How does arrestin respond to the phosphorylated state of rhodopsin? J Biol Chem 274:11451–11454PubMedCrossRefGoogle Scholar
  96. Vishnivetskiy SA, Schubert C, Climaco GC, Gurevich YV, Velez M-G, Gurevich VV (2000) An additional phosphate-binding element in arrestin molecule: implications for the mechanism of arrestin activation. J Biol Chem 275:41049–41057PubMedCrossRefGoogle Scholar
  97. Vishnivetskiy SA, Hirsch JA, Velez M-G, Gurevich YV, Gurevich VV (2002) Transition of arrestin in the active receptor-binding state requires an extended interdomain hinge. J Biol Chem 277:43961–43968PubMedCrossRefGoogle Scholar
  98. Vishnivetskiy SA, Francis DJ, Van Eps N, Kim M, Hanson SM, Klug CS, Hubbell WL, Gurevich VV (2010) The role of arrestin alpha-helix I in receptor binding. J Mol Biol 395:42–54PubMedCrossRefGoogle Scholar
  99. Vishnivetskiy SA, Baameur F, Findley KR, Gurevich VV (2013) Critical role of the central 139-loop in stability and binding selectivity of arrestin-1. J Biol Chem 288:11741–11750PubMedPubMedCentralCrossRefGoogle Scholar
  100. Wacker WB, Lipton MM (1965) Experimental allergic uveitis: homologous retina as uveitogenic antigen. Nature 206:253–254PubMedCrossRefGoogle Scholar
  101. Wacker WB, Donoso LA, Kalsow CM, Yankeelov JA Jr, Organisciak DT (1977) Experimental allergic uveitis. Isolation, characterization, and localization of a soluble uveitopathogenic antigen from bovine retina. J Immunol 119:1949–1958PubMedGoogle Scholar
  102. Wilden U (1995) Duration and amplitude of the light-induced cGMP hydrolysis in vertebrate photoreceptors are regulated by multiple phosphorylation of rhodopsin and by arrestin binding. Biochemistry 34:1446–1454PubMedCrossRefGoogle Scholar
  103. Wilden U, Hall SW, Kühn H (1986) 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 83:1174–1178PubMedPubMedCentralCrossRefGoogle Scholar
  104. Xiao K, McClatchy DB, Shukla AK, Zhao Y, Chen M, Shenoy SK, Yates JR, Lefkowitz RJ (2007) Functional specialization of beta-arrestin interactions revealed by proteomic analysis. Proc Natl Acad Sci USA 104:12011–12016PubMedPubMedCentralCrossRefGoogle Scholar
  105. Yamaki K, Takahashi Y, Sakuragi S, Matsubara K (1987) Molecular cloning of the S-antigen cDNA from bovine retina. Biochem Biophys Res Commun 142:904–910PubMedCrossRefGoogle Scholar
  106. Yang F, Yu X, Liu C, Qu CX, Gong Z, Liu HD, Li FH, Wang HM, He DF, Yi F, Song C, Tian CL, Xiao KH, Wang JY, Sun JP (2015) Phospho-selective mechanisms of arrestin conformations and functions revealed by unnatural amino acid incorporation and (19)F-NMR. Nat Commun 6:8202PubMedPubMedCentralCrossRefGoogle Scholar
  107. Zhan X, Gimenez LE, Gurevich VV, Spiller BW (2011a) Crystal structure of arrestin-3 reveals the basis of the difference in receptor binding between two non-visual arrestins. J Mol Biol 406:467–478PubMedPubMedCentralCrossRefGoogle Scholar
  108. Zhan X, Kaoud TS, Dalby KN, Gurevich VV (2011b) Nonvisual arrestins function as simple scaffolds assembling the MKK4-JNK3alpha2 signaling complex. Biochemistry 50:10520–10529PubMedPubMedCentralCrossRefGoogle Scholar
  109. Zhan X, Kaoud TS, Kook S, Dalby KN, Gurevich VV (2013) JNK3 enzyme binding to arrestin-3 differentially affects the recruitment of upstream mitogen-activated protein (MAP) kinase kinases. J Biol Chem 288:28535–28547PubMedPubMedCentralCrossRefGoogle Scholar
  110. Zhan X, Stoy H, Kaoud TS, Perry NA, Chen Q, Perez A, Els-Heindl S, Slagis JV, Iverson TM, Beck-Sickinger AG, Gurevich EV, Dalby KN, Gurevich VV (2016) Peptide mini-scaffold facilitates JNK3 activation in cells. Sci Rep 6:21025PubMedPubMedCentralCrossRefGoogle Scholar
  111. Zhuang T, Chen Q, Cho M-K, Vishnivetskiy SA, Iverson TI, Gurevich VV, Hubbell WL (2013) Involvement of distinct arrestin-1 elements in binding to different functional forms of rhodopsin. Proc Nat Acad Sci USA 110:942–947PubMedCrossRefGoogle Scholar
  112. Zhuo Y, Vishnivetskiy SA, Zhan X, Gurevich VV, Klug CS (2014) Identification of receptor binding-induced conformational changes in non-visual arrestins. J Biol Chem 289:20991–21002PubMedPubMedCentralCrossRefGoogle Scholar
  113. Zuckerman R, Cheasty JE (1986) A 48 kDa protein arrests cGMP phosphodiesterase activation in retinal rod disk membranes. FEBS Lett 207:35–41PubMedCrossRefGoogle Scholar
  114. Zuckerman R, Cheasty JE (1988) Sites of arrestin action during the quench phenomenon in retinal rods. FEBS Lett 238:379–384PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of PharmacologyVanderbilt UniversityNashvilleUSA

Personalised recommendations