Arrestins: structural disorder creates rich functionality

Abstract

Arrestins are soluble relatively small 44–46 kDa proteins that specifically bind hundreds of active phosphorylated GPCRs and dozens of non-receptor partners. There are binding partners that demonstrate preference for each of the known arrestin conformations: free, receptor-bound, and microtubule-bound. Recent evidence suggests that conformational flexibility in every functional state is the defining characteristic of arrestins. Flexibility, or plasticity, of proteins is often described as structural disorder, in contrast to the fixed conformational order observed in high-resolution crystal structures. However, protein-protein interactions often involve highly flexible elements that can assume many distinct conformations upon binding to different partners. Existing evidence suggests that arrestins are no exception to this rule: their flexibility is necessary for functional versatility. The data on arrestins and many other multi-functional proteins indicate that in many cases, “order” might be artificially imposed by highly non-physiological crystallization conditions and/or crystal packing forces. In contrast, conformational flexibility (and its extreme case, intrinsic disorder) is a more natural state of proteins, representing true biological order that underlies their physiologically relevant functions.

Keywords

arrestin / GPCR / crystal structure / NMR / EPR / disorder / protein-protein interactions

References

[1] Agarwal PK (2005) Role of protein dynamics in reaction rate enhancement by enzymes. J Am Chem Soc 127:15248–15256

[2] 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 50:3749–3763

[3] Artymiuk PJ, Blake CC, Grace DE, Oatley SJ, Phillips DC, Sternberg MJ (1979) Crystallographic studies of the dynamic properties of lysozyme. Nature 280:563–568

[4] 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 267:17882–17890

[5] Barak LS, Ferguson SS, Zhang J, Caron MG (1997) A betaarrestin/green fluorescent protein biosensor for detecting G protein-coupled receptor activation. J Biol Chem 272:27497–27500

[6] 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 dominantnegative arrestin-3 mutant. J Biol Chem 287:19653–19664

[7] Buljan M, Chalancon G, Dunker AK, Bateman A, Balaji S, Fuxreiter M, Babu MM (2013) Alternative splicing of intrinsically disordered regions and rewiring of protein interactions. Curr Opin Struct Biol 23:443–450

[8] Carpenter B, Nehmé R, Warne T, Leslie AG, Tate CG (2016) Structure of the adenosine A(2A) receptor bound to an engineered G protein. Nature 536:104–107

[9] Carter JM, Gurevich VV, Prossnitz ER, Engen JR (2005) Conformational differences between arrestin2 and pre-activated mutants as revealed by hydrogen exchange mass spectrometry. J Mol Biol 351:865–878

[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 277:9043–9048

[11] Chen Q, Perry NA, Vishnivetskiy SA, Berndt S, Gilbert NC, Zhuo Y, Singh PK, Tholen J, Ohi MD, Gurevich EV (2017) Structural basis of arrestin-3 activation and signaling. Nat Commun 8:1427

[12] Coffa S, Breitman M, Hanson SM, Callaway K, Kook S, Dalby KN, Gurevich VV (2011a) The effect of arrestin conformation on the recruitment of c-Raf1, MEK1, and ERK1/2 activation. PLoS ONE 6:e28723

[13] Coffa S, Breitman M, Spiller BW, Gurevich VV (2011b) A single mutation in arrestin-2 prevents ERK1/2 activation by reducing c-Raf1 binding. Biochemistry 50:6951–6958

[14] Danial NN, Korsmeyer SJ (2004) Cell death: critical control points. Cell 116:205–219

[15] Daniel RM, Dines M, Petach HH (1996) The denaturation and degradation of stable enzymes at high temperatures. Biochem J 317:1–11

[16] Disfani FM, Hsu WL, Mizianty MJ, Oldfield CJ, Xue B, Dunker AK, Uversky VN, Kurgan L (2012) MoRFpred, a computational tool for sequence-based prediction and characterization of short disorder-to-order transitioning binding regions in proteins. Bioinformatics 28:i75–83

[17] Dosztanyi Z, Csizmok V, Tompa P, Simon I (2005) IUPred: web server for the prediction of intrinsically unstructured regions of proteins based on estimated energy content. Bioinformatics 21:3433–3434

[18] Dosztanyi Z, Meszaros B, Simon I (2009) ANCHOR: web server for predicting protein binding regions in disordered proteins. Bioinformatics 25:2745–2746

[19] Dunker AK, Obradovic Z (2001) The protein trinity—linking function and disorder. Nat Biotechnol 19:805–806

[20] Dunker AK, Lawson JD, Brown CJ, Williams RM, Romero P, Oh JS, Oldfield CJ, Campen AM, Ratliff CM, Hipps KW (2001) Intrinsically disordered protein. J Mol Graph Model 19:26–59

[21] Dyson HJ, Wright PE (2002) Coupling of folding and binding for unstructured proteins. Curr Opin Struct Biol 12:54–60

[22] Eisenmesser EZ, Millet O, Labeikovsky W, Korzhnev DM, Wolf-Watz M, Bosco DA, Skalicky JJ, Kay LE, Kern D (2005) Intrinsic dynamics of an enzyme underlies catalysis. Nature 438:117–121

[23] 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 274:768–770

[24] Fernández-Arenas E, Calleja E, Martínez-Martín N, Gharbi SI, Navajas R, García-Medel N, Penela P, Alcamí A, Mayor FJ, Albar JP (2014) β-Arrestin-1 mediates the TCR-triggered rerouting of distal receptors to the immunological synapse by a PKC-mediated mechanism. EMBO J 33(6):559–577

[25] Frauenfelder H, Petsko GA, Tsernoglou D (1979) Temperaturedependent X-ray diffraction as a probe of protein structural dynamics. Nature 280:558–563

[26] Giver L, Gershenson A, Freskgard PO, Arnold FH (1998) Directed evolution of a thermostable esterase. Proc Natl Acad Sci USA 95:12809–12813

[27] 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 383:447–450

[28] 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 391:918–921

[29] 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 416:611–618

[30] Granzin J, Stadler A, Cousin A, Schlesinger R, Batra-Safferling R (2015) Structural evidence for the role of polar core residue Arg175 in arrestin activation. Sci Rep 5:15808

[31] Gurevich VV (1998) The selectivity of visual arrestin for lightactivated phosphorhodopsin is controlled by multiple nonredundant mechanisms. J Biol Chem 273:15501–15506

[32] Gurevich VV, Benovic JL (1992) Cell-free expression of visual arrestin. Truncation mutagenesis identifies multiple domains involved in rhodopsin interaction. J Biol Chem 267:21919–21923

[33] Gurevich VV, Benovic JL (1993) Visual arrestin interaction with rhodopsin: sequential multisite binding ensures strict selectivity towards light-activated phosphorylated rhodopsin. J Biol Chem 268:11628–11638

[34] Gurevich VV, Benovic JL (1995) Visual arrestin binding to rhodopsin: diverse functional roles of positively charged residues within the phosphorylation-recignition region of arrestin. J Biol Chem 270:6010–6016

[35] Gurevich VV, Benovic JL (1997) Mechanism of phosphorylationrecognition by visual arrestin and the transition of arrestin into a high affinity binding state. Mol Pharmacol 51:161–169

[36] Gurevich VV, Gurevich EV (2003) The new face of active receptor bound arrestin attracts new partners. Structure 11:1037–1042

[37] Gurevich VV, Gurevich EV (2004) The molecular acrobatics of arrestin activation. Trends Pharmacol Sci 25:105–111

[38] Gurevich EV, Gurevich VV (2006) Arrestins are ubiquitous regulators of cellular signaling pathways. Genome Biol 7:236

[39] Gurevich VV, Gurevich EV (2014) Arrestin makes T cells stop and become active. EMBO J 33:531–533

[40] 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 269:8721–8727

[41] Gurevich VV, Hanson SM, Song X, Vishnivetskiy SA, Gurevich EV (2011) The functional cycle of visual arrestins in photoreceptor cells. Prog Retin Eye Res 30:405–430

[42] Habchi J, Tompa P, Longhi S, Uversky VN (2014) Introducing protein intrinsic disorder. Chem Rev 114:6561–6588

[43] Han M, Gurevich VV, Vishnivetskiy SA, Sigler PB, Schubert C (2001) Crystal structure of beta-arrestin at 1.9 A: possible mechanism of receptor binding and membrane translocation. Structure 9:869–880

[44] Hanson SM, Gurevich VV (2006) The differential engagement of arrestin surface charges by the various functional forms of the receptor. J Biol Chem 281:3458–3462

[45] Hanson SM, Francis DJ, Vishnivetskiy SA, Klug CS, Gurevich VV (2006a) Visual arrestin binding to microtubules involves a distinct conformational change. J Biol Chem 281:9765–9772

[46] 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 103:4900–4905

[47] 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 368:375–387

[48] Hirsch JA, Schubert C, Gurevich VV, Sigler PB (1999) The 2.8 A crystal structure of visual arrestin: a model for arrestin’s regulation. Cell 97:257–269

[49] Hoffmann C, Gaietta G, Bunemann M, Adams SR, Oberdorff-Maass S, Behr B, Vilardaga JP, Tsien RY, Ellisman MH, Lohse MJ (2005) A FlAsH-based FRET approach to determine G protein-coupled receptor activation in living cells. Nat Methods 2:171–176

[50] Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14(1):33–38

[51] Iakoucheva LM, Brown CJ, Lawson JD, Obradovic Z, Dunker AK (2002) Intrinsic disorder in cell-signaling and cancer-associated proteins. J Mol Biol 323:573–584

[52] Iakoucheva LM, Radivojac P, Brown CJ, O’Connor TR, Sikes JG, Obradovic Z, Dunker AK (2004) The importance of intrinsic disorder for protein phosphorylation. Nucleic Acids Res 32:1037–1049

[53] Indrischek H, Prohaska SJ, Gurevich VV, Gurevich EV, Stadler PF (2017) Uncovering missing pieces: duplication and deletion history of arrestins in deuterostomes. BMC Evol Biol 17:163

[54] Kang DS, Kern RC, Puthenveedu MA, von Zastrow M, Williams JC, Benovic JL (2009) Structure of an arrestin2-clathrin complex reveals a novel clathrin binding domain that modulates receptor trafficking. J Biol Chem 284:29860–29872

[55] Kang Y, Zhou XE, Gao X, He Y, Liu W, Ishchenko A, Barty A, White TA, Yefanov O, Han GW (2015) Crystal structure of rhodopsin bound to arrestin determined by femtosecond X-ray laser. Nature 523:561–567

[56] Kim YM, Barak LS, Caron MG, Benovic JL (2002) Regulation of arrestin-3 phosphorylation by casein kinase II. J Biol Chem 277:16837–16846

[57] Kim M, Vishnivetskiy SA, Van Eps N, Alexander NS, Cleghorn WM, Zhan X, Hanson SM, Morizumi T, Ernst OP, Meiler J (2012) Conformation of receptor-bound visual arrestin. Proc Natl Acad Sci USA 109:18407–18412

[58] Kim YJ, Hofmann KP, Ernst OP, Scheerer P, Choe HW, Sommer ME (2013) Crystal structure of pre-activated arrestin p44. Nature 497:142–146

[59] Kook S, Zhan X, Kaoud TS, Dalby KN, Gurevich VV, Gurevich EV (2013) Arrestin-3 binds JNK1α1 and JNK2α2 and facilitates the activation of these ubiquitous JNK isoforms in cells via scaffolding. J Biol Chem 288:37332–37342

[60] Kook S, Zhan X, Cleghorn WM, Benovic JL, Gurevich VV, Gurevich EV (2014) Caspase-cleaved arrestin-2 and BID cooperatively facilitate cytochrome C release and cell death. Cell Death Differ 21:172–184

[61] Kovoor A, Celver J, Abdryashitov RI, Chavkin C, Gurevich VV (1999) Targeted construction of phosphorylation-independent b-arrestin mutants with constitutive activity in cells. J Biol Chem 274:6831–6834

[62] Krupnick JG, Gurevich VV, Benovic JL (1997) Mechanism of quenching of phototransduction. Binding competition between arrestin and transducin for phosphorhodopsin. J Biol Chem 272:18125–18131

[63] 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 176:473–478

[64] Lally CC, Bauer B, Selent J, Sommer ME (2017) C-edge loops of arrestin function as a membrane anchor. Nat Commun 8:14258

[65] 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 Natl Acad Sci USA 96:3712–3717

[66] Lawler S, Fleming Y, Goedert M, Cohen P (1998) Synergistic activation of SAPK1/JNK1 by two MAP kinase kinases in vitro. Curr Biol 8:1387–1390

[67] Lee MH, Appleton KM, Strungs EG, Kwon JY, Morinelli TA, Peterson YK, Laporte SA, Luttrell LM (2016) The conformational signature of beta-arrestin2 predicts its trafficking and signalling functions. Nature 531:665–668

[68] Levchenko A, Bruck J, Sternberg PW (2004) Regulatory modules that generate biphasic signal response in biological systems. Syst Biol (Stevenage) 1:139–148

[69] Lin FT, Krueger KM, Kendall HE, Daake Y, Fredericks ZL, Pitcher JA, Lefkowitz RJ (1997) Clathrin-mediated endocytosis of the betaadrenergic receptor is regulated by phosphorylation/dephosphorylation of beta-arrestin1. J Biol Chem 272:31051–31057

[70] Lin FT, Chen W, Shenoy S, Cong M, Exum ST, Lefkowitz RJ (2002) Phosphorylation of beta-arrestin2 regulates its function in internalization of beta(2)-adrenergic receptors. Biochemistry 41:10692–10699

[71] Lüthi AU, Martin SJ (2007) The CASBAH: a searchable database of caspase substrates. Cell Death Differ 14:641–650

[72] 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 98:2449–2454

[73] Ma B, Kumar S, Tsai CJ, Nussinov R (1999) Folding funnels and binding mechanisms. Protein Eng 12:713–720

[74] Manglik A, Kobilka B (2014) The role of protein dynamics in GPCR function: insights from the β2AR and rhodopsin. Curr Opin Cell Biol 27:136–143

[75] Manglik A, Kim TH, Masureel M, Altenbach C, Yang Z, Hilger D, Lerch MT, Kobilka TS, Thian FS, Hubbell WL (2015) Structural insights into the dynamic process of beta2-adrenergic receptor signaling. Cell 161:1101–1111

[76] McDonald PH, Chow CW, Miller WE, Laporte SA, Field ME, Lin FT, Davis RJ, Lefkowitz RJ (2000) Beta-arrestin 2: a receptorregulated MAPK scaffold for the activation of JNK3. Science 290:1574–1577

[77] Mendez A, Burns ME, Roca A, Lem J, Wu LW, Simon MI, Baylor DA, Chen J (2000) Rapid and reproducible deactivation of rhodopsin requires multiple phosphorylation sites. Neuron 28:153–164

[78] Milano SK, Pace HC, Kim YM, Brenner C, Benovic JL (2002) Scaffolding functions of arrestin-2 revealed by crystal structure and mutagenesis. Biochemistry 41:3321–3328

[79] Milano SK, Kim YM, Stefano FP, Benovic JL, Brenner C (2006) Nonvisual arrestin oligomerization and cellular localization are regulated by inositol hexakisphosphate binding. J Biol Chem 281:9812–9823

[80] 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 110:9463–9468

[81] Modzelewska A, Filipek S, Palczewski K, Park PS (2006) Arrestin interaction with rhodopsin: conceptual models. Cell Biochem Biophys 46:1–15

[82] Nobles KN, Guan Z, Xiao K, Oas TG, Lefkowitz RJ (2007) The active conformation of beta-arrestin1: direct evidence for the phosphate sensor in the N-domain and conformational differences in the active states of beta-arrestins1 and-2. J Biol Chem 282:21370–21381

[83] Nuber S, Zabel U, Lorenz K, Nuber A, Milligan G, Tobin AB, Lohse MJ, Hoffmann C (2016) beta-Arrestin biosensors reveal a rapid, receptor-dependent activation/deactivation cycle. Nature 531:661–664

[84] Oldfield CJ, Cheng Y, Cortese MS, Romero P, Uversky VN, Dunker AK (2005) Coupled folding and binding with alpha-helix-forming molecular recognition elements. Biochemistry 44:12454–12470

[85] Ostermaier MK, Peterhans C, Jaussi R, Deupi X, Standfuss J (2014) Functional map of arrestin-1 at single amino acid resolution. Proc Natl Acad Sci USA 111:1825–1830

[86] Palczewski K, Pulvermuller A, Buczylko J, Hofmann KP (1991) Phosphorylated rhodopsin and heparin induce similar conformational changes in arrestin. J Biol Chem 266:18649–18654

[87] Pan L, Gurevich EV, Gurevich VV (2003) The nature of the arrestin x receptor complex determines the ultimate fate of the internalized receptor. J Biol Chem 278:11623–11632

[88] Pejaver V, Hsu WL, Xin F, Dunker AK, Uversky VN, Radivojac P (2014) The structural and functional signatures of proteins that undergo multiple events of post-translational modification. Protein Sci 23:1077–1093

[89] Peng K, Vucetic S, Radivojac P, Brown CJ, Dunker AK, Obradovic Z (2005) Optimizing long intrinsic disorder predictors with protein evolutionary information. J Bioinform Comput Biol 3:35–60

[90] Peng K, Radivojac P, Vucetic S, Dunker AK, Obradovic Z (2006) Length-dependent prediction of protein intrinsic disorder. BMC Bioinform 7:208

[91] Peterson YK, Luttrell LM (2017) The diverse roles of arrestin scaffolds in G protein-coupled receptor signaling. Pharmacol Rev 69:256–297

[92] Privalov PL, Khechinashvili NN (1974) A thermodynamic approach to the problem of stabilization of globular protein structure: a calorimetric study. J Mol Biol 86:665–684

[93] Puig J, Arendt A, Tomson FL, Abdulaeva G, Miller R, Hargrave PA, McDowell JH (1995) Synthetic phosphopeptide from rhodopsin sequence induces retinal arrestin binding to photoactivated unphosphorylated rhodopsin. FEBS Lett 362:185–188

[94] Pulvermuller A, Maretzki D, Rudnicka-Nawrot M, Smith WC, Palczewski K, Hofmann KP (1997) Functional differences in the interaction of arrestin and its splice variant, p44, with rhodopsin. Biochemistry 36:9253–9260

[95] Radivojac P, Iakoucheva LM, Oldfield CJ, Obradovic Z, Uversky VN, Dunker AK (2007) Intrinsic disorder and functional proteomics. Biophys J 92:1439–1456

[96] Rasmussen SG, DeVree BT, Zou Y, Kruse AC, Chung KY, Kobilka TS, Thian FS, Chae PS, Pardon E, Calinski D (2011) Crystal structure of the β2 adrenergic receptor-Gs protein complex. Nature 477:549–555

[97] Romero PR, Zaidi S, Fang YY, Uversky VN, Radivojac P, Oldfield CJ, Cortese MS, Sickmeier M, LeGall T, Obradovic Z (2006) Alternative splicing in concert with protein intrinsic disorder enables increased functional diversity in multicellular organisms. Proc Natl Acad Sci USA 103:8390–8395

[98] Ruvinov S, Wang L, Ruan B, Almog O, Gilliland GL, Eisenstein E, Bryan PN (1997) Engineering the independent folding of the subtilisin BPN’ prodomain: analysis of two-state folding versus protein stability. Biochemistry 36:10414–10421

[99] Savage HJ, Elliott CJ, Freeman CM, Finney JL (1993) Lost hydrogen-bonds and buried surface-area—rationalizing stability in globular-proteins. J Chem Soc Faraday Trans 89:2609–2617

[100] Scheerer P, Park JH, Hildebrand PW, Kim YJ, Krauss N, Choe HW, Hofmann KP, Ernst OP (2008) Crystal structure of opsin in its G-protein-interacting conformation. Nature 455:497–502

[101] 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 28:1770–1775

[102] Sensoy O, Moreira IS, Morra G (2016) Understanding the differential selectivity of arrestins toward the phosphorylation state of the receptor. ACS Chem Neurosci 7:1212–1224

[103] Shatsky M, Nussinov R, Wolfson HJ (2004) A method for simultaneous alignment of multiple protein structures. Proteins 56:143–156

[104] Shoemaker BA, Portman JJ, Wolynes PG (2000) Speeding molecular recognition by using the folding funnel: the fly-casting mechanism. Proc Natl Acad Sci USA 97:8868–8873

[105] Shukla AK, Manglik A, Kruse AC, Xiao K, Reis RI, Tseng WC, Staus DP, Hilger D, Uysal S, Huang LY (2013) Structure of active β-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide. Nature 497:137–141

[106] Smith WC, Milam AH, Dugger D, Arendt A, Hargrave PA, Palczewski K (1994) A splice variant of arrestin. Molecular cloning and localization in bovine retina. J Biol Chem 269:15407–15410

[107] Sommer ME, Farrens DL, McDowell JH, Weber LA, Smith WC (2007) Dynamics of arrestin-rhodopsin interactions: loop movement is involved in arrestin activation and receptor binding. J Biol Chem 282:25560–25568

[108] 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 281:21491–21499

[109] Song X, Coffa S, Fu H, Gurevich VV (2009a) How does arrestin assemble MAPKs into a signaling complex? J Biol Chem 284:685–695

[110] Song X, Vishnivetskiy SA, Gross OP, Emelianoff K, Mendez A, Chen J, Gurevich EV, Burns ME, Gurevich VV (2009b) Enhanced arrestin facilitates recovery and protects rod photoreceptors deficient in rhodopsin phosphorylation. Curr Biol 19:700–705

[111] Song X, Vishnivetskiy SA, Seo J, Chen J, Gurevich EV, Gurevich VV (2011) Arrestin-1 expression in rods: balancing functional performance and photoreceptor health. Neuroscience 174:37–49

[112] Standfuss J, Xie G, Edwards PC, Burghammer M, Oprian DD, Schertler GF (2007) Crystal structure of a thermally stable rhodopsin mutant. J Mol Biol 372:1179–1188

[113] Sterne-Marr R, Gurevich VV, Goldsmith P, Bodine RC, Sanders C, Donoso LA, Benovic JL (1993) Polypeptide variants of betaarrestin and arrestin3. J Biol Chem 268:15640–15648

[114] Sugase K, Dyson HJ, Wright PE (2007) Mechanism of coupled folding and binding of an intrinsically disordered protein. Nature 447:1021–1025

[115] 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 2.3Å: evolution of receptor specificity. J Mol Biol 354:1069–1080

[116] Tang KES, Dill KA (1998) Native protein fluctuations: The conformational-motion temperature and the inverse correlation of protein flexibility with protein stability. J Biomol Struct Dyn 16:397–411

[117] Taverna DM, Goldstein RA (2002) Why are proteins marginally stable? Proteins 46:105–109

[118] ter Haar E, Harrison SC, Kirchhausen T (2000) Peptide-in-groove interactions link target proteins to the beta-propeller of clathrin. Proc Natl Acad Sci USA 97:1096–1100

[119] Tompa P (2012) Intrinsically disordered proteins: a 10-year recap. Trends Biochem Sci 37:509–516

[120] Tsou CL (1998a) Active site flexibility in enzyme catalysis. Enzyme Eng XIV 864:1–8

[121] Tsou CL (1998b) The role of active site flexibility in enzyme catalysis. Biochemistry 63:253–258

[122] Uversky VN (2013) Unusual biophysics of intrinsically disordered proteins. Biochim Biophys Acta 1834:932–951

[123] Uversky VN (2015) Functional roles of transiently and intrinsically disordered regions within proteins. FEBS J 282:1182–1189

[124] Uversky VN (2016) Dancing protein clouds: the strange biology and chaotic physics of intrinsically disordered proteins. J Biol Chem 291:6681–6688

[125] Uversky VN, Dunker AK (2010) Understanding protein non-folding. Biochim Biophys Acta 1804:1231–1264

[126] Uversky VN, Gillespie JR, Fink AL (2000) Why are “natively unfolded” proteins unstructured under physiologic conditions? Proteins 41:415–427

[127] Uversky VN, Oldfield CJ, Dunker AK (2005) Showing your ID: intrinsic disorder as an ID for recognition, regulation and cell signaling. J Mol Recognit 18:343–384

[128] Uversky VN, Oldfield CJ, Dunker AK (2008) Intrinsically disordered proteins in human diseases: introducing the D2 concept. Annu Rev Biophys 37:215–246

[129] Uversky VN, Dave V, Iakoucheva LM, Malaney P, Metallo SJ, Pathak RR, Joerger AC (2014) Pathological unfoldomics of uncontrolled chaos: intrinsically disordered proteins and human diseases. Chem Rev 114:6844–6879

[130] van der Lee R, Buljan M, Lang B, Weatheritt RJ, Daughdrill GW, Dunker AK, Fuxreiter M, Gough J, Gsponer J, Jones DT (2014) Classification of intrinsically disordered regions and proteins. Chem Rev 114:6589–6631

[131] Varley PG, Pain RH (1991) Relation between stability, dynamics and enzyme-activity in 3-phosphoglycerate kinases from yeast and thermus-thermophilus. J Mol Biol 220:531–538

[132] 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 274:11451–11454

[133] 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 275:41049–41057

[134] 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 277:43961–43968

[135] Vishnivetskiy SA, Raman D, Wei J, Kennedy MJ, Hurley JB, Gurevich VV (2007) Regulation of arrestin binding by rhodopsin phosphorylation level. J Biol Chem 282:32075–32083

[136] Vishnivetskiy SA, Francis DJ, Van Eps N, Kim M, Hanson SM, Klug CS, Hubbell WL, Gurevich VV (2010) The role of arrestin alphahelix I in receptor binding. J Mol Biol 395:42–54

[137] Vishnivetskiy SA, Gimenez LE, Francis DJ, Hanson SM, Hubbell WL, Klug CS, Gurevich VV (2011) Few residues within an extensive binding interface drive receptor interaction and determine the specificity of arrestin proteins. J Biol Chem 286:24288–24299

[138] Vishnivetskiy SA, Chen Q, Palazzo MC, Brooks EK, Altenbach C, Iverson TM, Hubbell WL, Gurevich VV (2013) Engineering visual arrestin-1 with special functional characteristics. J Biol Chem 288:11741–11750

[139] Vogl T, Jatzke C, Hinz HJ, Benz J, Huber R (1997) Thermodynamic stability of annexin V E17G: equilibrium parameters from an irreversible unfolding reaction. Biochemistry 36:1657–1668

[140] Wagner G,Wuthrich K (1979) Correlation between the amide protonexchange rates and the denaturation temperatures in globularproteins related to the basic pancreatic trypsin-inhibitor. J Mol Biol 130:31–37

[141] 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 34:1446–1454

[142] 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 USA 83:1174–1178

[143] Williams PD, Pollock DD, Goldstein RA (2006) Functionality and the evolution of marginal stability in proteins: inferences from lattice simulations. Evol Bioinform 2:91–101

[144] Wrba A, Schweiger A, Schultes V, Jaenicke R, Zavodszky P (1990) Extremely thermostable D-glyceraldehyde-3-phosphate dehydrogenase from the eubacterium thermotoga-maritima. Biochemistry 29:7584–7592

[145] Wright PE, Dyson HJ (1999) Intrinsically unstructured proteins: reassessing the protein structure-function paradigm. J Mol Biol 293:321–331

[146] Xiao K, Shenoy SK, Nobles K, Lefkowitz RJ (2004) Activationdependent conformational changes in {beta}-arrestin 2. J Biol Chem 279:55744–55753

[147] Xue B, Dunbrack RL, Williams RW, Dunker AK, Uversky VN (2010) PONDR-FIT: a meta-predictor of intrinsically disordered amino acids. Biochim Biophys Acta 1804:996–1010

[148] Yang F, Yu X, Liu C, Qu CX, Gong Z, Liu HD, Li FH, Wang HM, He DF, Yi F (2015) Phospho-selective mechanisms of arrestin conformations and functions revealed by unnatural amino acid incorporation and (19)F-NMR. Nat Commun 6:8202

[149] Yun Y, Kim DK, Seo MD, Kim KM, Chung KY (2015) Different conformational dynamics of beta-arrestin1 and beta-arrestin2 analyzed by hydrogen/deuterium exchange mass spectrometry. Biochem Biophys Res Commun 457:50–57

[150] Zavodszky P, Kardos J, Svingor A, Petsko GA (1998) Adjustment of conformational flexibility is a key event in the thermal adaptation of proteins. Proc Natl Acad Sci USA 95:7406–7411

[151] Zhan X, Gimenez LE, Gurevich VV, Spiller BW (2011) Crystal structure of arrestin-3 reveals the basis of the difference in receptor binding between two non-visual arrestins. J Mol Biol 406:467–478

[152] Zhan X, Kaoud TS, Kook S, Dalby KN, Gurevich VV (2013) JNK3 binding to arrestin-3 differentially affects the recruitment of upstream MAP kinase kinases. J Biol Chem 288:28535–28547

[153] Zhan X, Perez A, Gimenez LE, Vishnivetskiy SA, Gurevich VV (2014) Arrestin-3 binds the MAP kinase JNK3α2 via multiple sites on both domains. Cell Signal 26:766–776

[154] Zhan X, Stoy H, Kaoud TS, Perry NA, Chen Q, Vucak G, Perez A, Els-Heindl S, Slagis JV, Iverson TM (2016) Peptide miniscaffold facilitates JNK3 activation in cells. Sci Rep 6:21025

[155] Zhou XE, He Y, de Waal PW, Gao X, Kang Y, Van Eps N, Yin Y, Pal K, Goswami D, White TA (2017) Structural identification of phosphorylation codes for arrestin recruitment by G proteincoupled receptors. Cell 170:457–469

[156] Zhuang T, Vishnivetskiy SA, Gurevich VV, Sanders CR (2010) Elucidation of IP6 and heparin interaction sites and conformational changes in arrestin-1 by solution NMR. Biochemistry 49:10473–10485

[157] Zhuang T, Chen Q, Cho M-K, Vishnivetskiy SA, Iverson TM, Gurevich VV, Sanders CR (2013a) Involvement of distinct arrestin-1 elements in binding to different functional forms of rhodopsin. Proc Natl Acad Sci USA 110:942–947

[158] 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 289:20991–21002

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