Skip to main content
SpringerLink
Log in

Dynamic Nature of Proteins is Critically Important for Their Function: GPCRs and Signal Transducers

  • Review
  • Published:
Applied Magnetic Resonance Aims and scope Submit manuscript

A Correction to this article was published on 04 November 2023

This article has been updated

Abstract

Proteins and their complexes in structures solved by X-ray crystallography or cryo-EM look rigid. While these structures yield very detailed information, they do not capture critically important property of proteins, their dynamic nature. The very fact that proteins function indicates that they must have moving parts. Structural studies have additional caveats: to obtain structures, proteins are often drastically engineered and placed into highly non-physiological conditions. In contrast to structural studies, biophysical methods, such as EPR and NMR spectroscopy, reveal protein and complex dynamics. Importantly, minimally mutated, virtually wild-type proteins can be used. Here, this issue is discussed using GPCRs and their signal transducers, G proteins and arrestins, as examples. To understand how proteins actually work in living cells, we must keep in mind the limitations of different methods and synthesize the information obtained by all of them.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Availability of Data and Materials

No new data are presented and no materials were used.

Change history

Notes

  1. We use systematic names of arrestin proteins, where the number after the dash indicates the order of cloning: arrestin-1 (historic names S-antigen, 48 kDa protein, visual or rod arrestin), arrestin-2 (β-arrestin or β-arrestin1), arrestin-3 (β-arrestin2 or hTHY-ARRX), and arrestin-4 (cone or X-arrestin).

References

  1. D.G. Lambright, J.P. Noel, H.E. Hamm, P.B. Sigler, Structural determinants for activation of the alpha-subunit of a heterotrimeric G protein. Nature 369(6482), 621–628 (1994)

    CAS  PubMed  Google Scholar 

  2. J.A. Hirsch, C. Schubert, V.V. Gurevich, P.B. Sigler, The 2.8 A crystal structure of visual arrestin: a model for arrestin’s regulation. Cell 97(2), 257–269 (1999)

    CAS  PubMed  Google Scholar 

  3. K. Palczewski, T. Kumasaka, T. Hori, C.A. Behnke, H. Motoshima, B.A. Fox, I. Le Trong, D.C. Teller, T. Okada, R.E. Stenkamp, M. Yamamoto, M. Miyano, Crystal structure of rhodopsin: a G protein-coupled receptor. Science 289(5480), 739–745 (2000)

    CAS  PubMed  Google Scholar 

  4. S.G. Rasmussen, H.J. Choi, D.M. Rosenbaum, T.S. Kobilka, F.S. Thian, P.C. Edwards, M. Burghammer, V.R. Ratnala, R. Sanishvili, R.F. Fischetti, G.F. Schertler, W.I. Weis, B.K. Kobilka, Crystal structure of the human beta2 adrenergic G-protein-coupled receptor. Nature 450(7168), 383–387 (2007)

    CAS  PubMed  Google Scholar 

  5. S.G. Rasmussen, B.T. DeVree, Y. Zou, A.C. Kruse, K.Y. Chung, T.S. Kobilka, F.S. Thian, P.S. Chae, E. Pardon, D. Calinski, J.M. Mathiesen, S.T. Shah, J.A. Lyons, M. Caffrey, S.H. Gellman, J. Steyaert, G. Skiniotis, W.I. Weis, R.K. Sunahara, B.K. Kobilka, Crystal structure of the β2 adrenergic receptor-Gs protein complex. Nature 477(7366), 549–555 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Y. Kang, X.E. Zhou, X. Gao, Y. He, W. Liu, A. Ishchenko, A. Barty, T.A. White, O. Yefanov, G.W. Han, Q. Xu, P.W. de Waal, J. Ke, M.H. Tan, C. Zhang, A. Moeller, G.M. West, B.D. Pascal, N. Van Eps, L.N. Caro, S.A. Vishnivetskiy, R.J. Lee, K.M. Suino-Powell, X. Gu, K. Pal, J. Ma, X. Zhi, S. Boutet, G.J. Williams, M. Messerschmidt, C. Gati, N.A. Zatsepin, D. Wang, D. James, S. Basu, S. Roy-Chowdhury, C.E. Conrad, J. Coe, H. Liu, S. Lisova, C. Kupitz, I. Grotjohann, R. Fromme, Y. Jiang, M. Tan, H. Yang, J. Li, M. Wang, Z. Zheng, D. Li, N. Howe, Y. Zhao, J. Standfuss, K. Diederichs, Y. Dong, C.S. Potter, B. Carragher, M. Caffrey, H. Jiang, H.N. Chapman, J.C. Spence, P. Fromme, U. Weierstall, O.P. Ernst, V. Katritch, V.V. Gurevich, P.R. Griffin, W.L. Hubbell, R.C. Stevens, V. Cherezov, K. Melcher, H.E. Xu, Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser. Nature 523(7562), 561–567 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  7. T. Zhuang, Q. Chen, M.-K. Cho, S.A. Vishnivetskiy, T.I. Iverson, V.V. Gurevich, W.L. Hubbell, C.R. Sanders, Involvement of distinct arrestin-1 elements in binding to different functional forms of rhodopsin. Proc. Nat. Acad. Sci. USA 110(3), 942–947 (2013)

    CAS  PubMed  Google Scholar 

  8. T. Zhuang, S.A. Vishnivetskiy, V.V. Gurevich, C.R. Sanders, Elucidation of inositol hexaphosphate and heparin interaction sites and conformational changes in arrestin-1 by solution nuclear magnetic resonance. Biochemistry 49(49), 10473–10485 (2010)

    CAS  PubMed  Google Scholar 

  9. M. Elgeti, W.L. Hubbell, DEER Analysis of GPCR conformational Heterogeneity. Biomolecules 11(6), 778 (2021)

    CAS  PubMed  PubMed Central  Google Scholar 

  10. D.L. Farrens, C. Altenbach, K. Yang, W.L. Hubbell, H.G. Khorana, Requirement of rigid-body motion of transmembrane helices for light activation of rhodopsin. Science 274(5288), 768–770 (1996)

    CAS  PubMed  Google Scholar 

  11. S.M. Hanson, E.S. Dawson, D.J. Francis, N. Van Eps, C.S. Klug, W.L. Hubbell, J. Meiler, V.V. Gurevich, A model for the solution structure of the rod arrestin tetramer. Structure 16, 924–934 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  12. S.M. Hanson, D.J. Francis, S.A. Vishnivetskiy, E.A. Kolobova, W.L. Hubbell, C.S. Klug, V.V. Gurevich, Differential interaction of spin-labeled arrestin with inactive and active phosphorhodopsin. Proc. Natl. Acad. Sci. USA 103, 4900–4905 (2006)

    CAS  PubMed  PubMed Central  Google Scholar 

  13. S.M. Hanson, N. Van Eps, D.J. Francis, C. Altenbach, S.A. Vishnivetskiy, V.Y. Arshavsky, C.S. Klug, W.L. Hubbell, V.V. Gurevich, Structure and function of the visual arrestin oligomer. EMBO J. 26, 1726–1736 (2007)

    CAS  PubMed  PubMed Central  Google Scholar 

  14. M. Kim, S.M. Hanson, S.A. Vishnivetskiy, X. Song, W.M. Cleghorn, W.L. Hubbell, V.V. Gurevich, Robust self-association is a common feature of mammalian visual arrestin-1. Biochemistry 50, 2235–2242 (2011)

    CAS  PubMed  Google Scholar 

  15. M. Kim, S.A. Vishnivetskiy, N. Van Eps, N.S. Alexander, W.M. Cleghorn, X. Zhan, S.M. Hanson, T. Morizumi, O.P. Ernst, J. Meiler, V.V. Gurevich, W.L. Hubbell, Conformation of receptor-bound visual arrestin. Proc. Nat. Acad. Sci. USA 109(45), 18407–18412 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  16. A. Manglik, T.H. Kim, M. Masureel, C. Altenbach, Z. Yang, D. Hilger, M.T. Lerch, T.S. Kobilka, F.S. Thian, W.L. Hubbell, R.S. Prosser, B.K. Kobilka, Structural insights into the dynamic process of β2-adrenergic receptor signaling. Cell 161(5), 1101–1111 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  17. W.M. Oldham, N. Van Eps, A.M. Preininger, W.L. Hubbell, H.E. Hamm, Mechanism of the receptor-catalyzed activation of heterotrimeric G proteins. Nat. Struct. Mol. Biol. 13(9), 772–777 (2006)

    CAS  PubMed  Google Scholar 

  18. N. Van Eps, L.N. Caro, T. Morizumi, A.K. Kusnetzow, M. Szczepek, K.P. Hofmann, T.H. Bayburt, S.G. Sligar, O.P. Ernst, W.L. Hubbell, Conformational equilibria of light-activated rhodopsin in nanodiscs. Proc. Natl. Acad. Sci. USA 114(16), E3268–E3275 (2017)

    PubMed  PubMed Central  Google Scholar 

  19. N. Van Eps, W.M. Oldham, H.E. Hamm, W.L. Hubbell, Structural and dynamical changes in an alpha-subunit of a heterotrimeric G protein along the activation pathway. Proc. Natl. Acad. Sci. USA 103(44), 16194–16199 (2006)

    PubMed  PubMed Central  Google Scholar 

  20. N. Van Eps, A.M. Preininger, N. Alexander, A.I. Kaya, S. Meier, J. Meiler, H.E. Hamm, W.L. Hubbell, Interaction of a G protein with an activated receptor opens the interdomain interface in the alpha subunit. Proc. Natl. Acad. Sci. USA 108(23), 9420–9424 (2011)

    PubMed  PubMed Central  Google Scholar 

  21. Y. Zhuo, S.A. Vishnivetskiy, X. Zhan, V.V. Gurevich, C.S. Klug, Identification of receptor binding-induced conformational changes in non-visual arrestins. J. Biol. Chem. 289(30), 20991–21002 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  22. V.V. Gurevich, E.V. Gurevich, The molecular acrobatics of arrestin activation. Trends Pharmacol. Sci 25, 59–112 (2004)

    Google Scholar 

  23. P. Samama, S. Cotecchia, T. Costa, R.J. Lefkowitz, A mutation-induced activated state of the beta 2-adrenergic receptor. Extending the ternary complex model. J. Biol. Chem. 268(7), 4625–4636 (1993)

    CAS  PubMed  Google Scholar 

  24. V. Cherezov, D.M. Rosenbaum, M.A. Hanson, S.G. Rasmussen, F.S. Thian, T.S. Kobilka, H.J. Choi, P. Kuhn, W.I. Weis, B.K. Kobilka, R.C. Stevens, High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor. Science 318(5854), 1258–1265 (2007)

    CAS  PubMed  PubMed Central  Google Scholar 

  25. S.G. Rasmussen, H.J. Choi, J.J. Fung, E. Pardon, P. Casarosa, P.S. Chae, B.T. Devree, D.M. Rosenbaum, F.S. Thian, T.S. Kobilka, A. Schnapp, I. Konetzki, R.K. Sunahara, S.H. Gellman, A. Pautsch, J. Steyaert, W.I. Weis, B.K. Kobilka, Structure of a nanobody-stabilized active state of the β(2) adrenoceptor. Nature 469(7329), 175–180 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  26. D.M. Rosenbaum, C. Zhang, J.A. Lyons, R. Holl, D. Aragao, D.H. Arlow, S.G. Rasmussen, H.J. Choi, B.T. Devree, R.K. Sunahara, P.S. Chae, S.H. Gellman, R.O. Dror, D.E. Shaw, W.I. Weis, M. Caffrey, P. Gmeiner, B.K. Kobilka, Structure and function of an irreversible agonist-β(2) adrenoceptor complex. Nature 469(7329), 236–240 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  27. M.T. Lerch, R.A. Matt, M. Masureel, M. Elgeti, K.K. Kumar, D. Hilger, B. Foys, B.K. Kobilka, W.L. Hubbell, Viewing rare conformations of the β2 adrenergic receptor with pressure-resolved DEER spectroscopy. Proc. Natl. Acad. Sci. USA 117(50), 31824–31831 (2020)

    CAS  PubMed  PubMed Central  Google Scholar 

  28. R.A. Dixon, B.K. Kobilka, D.J. Strader, J.L. Benovic, H.G. Dohlman, T. Frielle, M.A. Bolanowski, C.D. Bennett, E. Rands, R.E. Diehl, R.A. Mumford, E.E. Slater, I.S. Sigal, M.G. Caron, R.J. Lefkowitz, C.D. Strader, Cloning of the gene and cDNA for mammalian beta-adrenergic receptor and homology with rhodopsin. Nature 321, 75–79 (1986)

    CAS  PubMed  Google Scholar 

  29. G. Milligan, E. Kostenis, Heterotrimeric G-proteins: a short history. Br J. Pharmacol. 147, S46-55 (2006)

    CAS  PubMed  PubMed Central  Google Scholar 

  30. J.W. Wisler, K. Xiao, A.R. Thomsen, R.J. Lefkowitz, Recent developments in biased agonism. Curr. Opin. Cell Biol. 27, 18–24 (2014)

    CAS  PubMed  Google Scholar 

  31. C.M. Costa-Neto, L.T. Parreiras-E-Silva, M. Bouvier, A pluridimensional view of biased agonism. Mol. Pharmacol. 90(5), 587–595 (2016)

    CAS  PubMed  Google Scholar 

  32. S.M. DeWire, J.D. Violin, Biased ligands for better cardiovascular drugs: dissecting G-protein-coupled receptor pharmacology. Circ. Res. 109(2), 205–216 (2011)

    CAS  PubMed  Google Scholar 

  33. H. Indrischek, S.J. Prohaska, V.V. Gurevich, E.V. Gurevich, P.F. Stadler, Uncovering missing pieces: duplication and deletion history of arrestins in deuterostomes. BMC Evol. Biol. 17(1), 163 (2017)

    PubMed  PubMed Central  Google Scholar 

  34. D.S. Eiger, U. Pham, J. Gardner, C. Hicks, S. Rajagopal, GPCR systems pharmacology: a different perspective on the development of biased therapeutics. Am. J. Physiol. Cell Physiol. 322(5), C887-c895 (2022)

    PubMed  PubMed Central  Google Scholar 

  35. V.V. Gurevich, E.V. Gurevich, Biased GPCR signaling: possible mechanisms and inherent limitations. Pharmacol. Ther. 211, 107540 (2020)

    CAS  PubMed  PubMed Central  Google Scholar 

  36. L.M. Wingler, C. McMahon, D.P. Staus, R.J. Lefkowitz, A.C. Kruse, Distinctive activation mechanism for angiotensin receptor revealed by a synthetic nanobody. Cell 176(3), 479–490 (2019)

    CAS  PubMed  PubMed Central  Google Scholar 

  37. M. Natochin, M. Moussaif, N.O. Artemyev, Probing the mechanism of rhodopsin catalyzed transducin activation. J. Neurochem. 77, 202–210 (2001)

    CAS  PubMed  Google Scholar 

  38. R.O. Dror, T.J. Mildorf, D. Hilger, A. Manglik, D.W. Borhani, D.H. Arlow, A. Philippsen, N. Villanueva, Z. Yang, M.T. Lerch, W.L. Hubbell, B.K. Kobilka, R.K. Sunahara, D.E. Shaw, SIGNAL TRANSDUCTION. Structural basis for nucleotide exchange in heterotrimeric G proteins. Science 348(6241), 1361–1365 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  39. E.V. Gurevich, J.J. Tesmer, A. Mushegian, V.V. Gurevich, G protein-coupled receptor kinases: more than just kinases and not only for GPCRs. Pharmacol. Ther. 133(1), 40–46 (2012)

    CAS  PubMed  Google Scholar 

  40. A.D. Tóth, S. Prokop, P. Gyombolai, P. Várnai, A. Balla, V.V. Gurevich, L. Hunyady, G. Turu, Heterologous phosphorylation-induced formation of a stability lock permits regulation of inactive receptors by β-arrestins. J. Biol. Chem. 293(3), 876–892 (2018)

    PubMed  Google Scholar 

  41. C.V. Carman, J.L. Benovic, G-protein-coupled receptors: turn-ons and turn-offs. Curr. Opin. Neurobiol. 8, 335–344 (1998)

    CAS  PubMed  Google Scholar 

  42. V.V. Gurevich, E.V. Gurevich, Plethora of functions packed into 45 kDa arrestins: biological implications and possible therapeutic strategies. Cell. Mol. Life Sci. 76(22), 4413–4421 (2019)

    CAS  PubMed  Google Scholar 

  43. Y.K. Peterson, L.M. Luttrell, The diverse roles of arrestin scaffolds in G protein-coupled receptor signaling. Pharmacol. Rev. 69(3), 256–297 (2017)

    CAS  PubMed  PubMed Central  Google Scholar 

  44. M. Han, V.V. Gurevich, S.A. Vishnivetskiy, P.B. Sigler, C. Schubert, Crystal structure of beta-arrestin at 1.9 A: possible mechanism of receptor binding and membrane translocation. Structure 9(9), 869–880 (2001)

    CAS  PubMed  Google Scholar 

  45. R.B. Sutton, S.A. Vishnivetskiy, J. Robert, S.M. Hanson, D. Raman, B.E. Knox, M. Kono, J. Navarro, V.V. Gurevich, Crystal structure of cone arrestin at 2.3Å: evolution of receptor specificity. J. Mol. Biol. 354, 1069–1080 (2005)

    CAS  PubMed  Google Scholar 

  46. X. Zhan, L.E. Gimenez, V.V. Gurevich, B.W. Spiller, 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 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  47. S.K. Milano, H.C. Pace, Y.M. Kim, C. Brenner, J.L. Benovic, Scaffolding functions of arrestin-2 revealed by crystal structure and mutagenesis. Biochemistry 41(10), 3321–3328 (2002)

    CAS  PubMed  Google Scholar 

  48. J. Granzin, U. Wilden, H.W. Choe, J. Labahn, B. Krafft, G. Buldt, X-ray crystal structure of arrestin from bovine rod outer segments. Nature 391(6670), 918–921 (1998)

    CAS  PubMed  Google Scholar 

  49. C.L. Sander, J. Luu, K. Kim, D. Furkert, K. Jang, J. Reichenwallner, M. Kang, H.J. Lee, B.T. Eger, H.W. Choe, D. Fiedler, O.P. Ernst, Y.J. Kim, K. Palczewski, P.D. Kiser, Structural evidence for visual arrestin priming via complexation of phosphoinositols. Structure 30(2), 263–277 (2022)

    CAS  PubMed  Google Scholar 

  50. S.A. Vishnivetskiy, D.J. Francis, N. Van Eps, M. Kim, S.M. Hanson, C.S. Klug, W.L. Hubbell, V.V. Gurevich, The role of arrestin alpha-helix I in receptor binding. J. Mol. Biol. 395, 42–54 (2010)

    CAS  PubMed  Google Scholar 

  51. S.M. Hanson, W.M. Cleghorn, D.J. Francis, S.A. Vishnivetskiy, D. Raman, X. Song, K.S. Nair, V.Z. Slepak, C.S. Klug, V.V. Gurevich, Arrestin mobilizes signaling proteins to the cytoskeleton and redirects their activity. J. Mol. Biol. 368(2), 375–387 (2007)

    CAS  PubMed  PubMed Central  Google Scholar 

  52. S.M. Hanson, D.J. Francis, S.A. Vishnivetskiy, C.S. Klug, V.V. Gurevich, Visual arrestin binding to microtubules involves a distinct conformational change. J. Biol. Chem. 281, 9765–9772 (2006)

    CAS  PubMed  Google Scholar 

  53. N. Wu, S.M. Hanson, D.J. Francis, S.A. Vishnivetskiy, M. Thibonnier, C.S. Klug, M. Shoham, V.V. Gurevich, Arrestin binding to calmodulin: a direct interaction between two ubiquitous signaling proteins. J. Mol. Biol. 364, 955–963 (2006)

    CAS  PubMed  PubMed Central  Google Scholar 

  54. S.A. Vishnivetskiy, L.E. Gimenez, D.J. Francis, S.M. Hanson, W.L. Hubbell, C.S. Klug, V.V. Gurevich, Few residues within an extensive binding interface drive receptor interaction and determine the specificity of arrestin proteins. J. Biol. Chem. 286, 24288–24299 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  55. X. Song, D. Raman, E.V. Gurevich, S.A. Vishnivetskiy, V.V. Gurevich, 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 (2006)

    CAS  PubMed  Google Scholar 

  56. M. Breitman, S. Kook, L.E. Gimenez, B.N. Lizama, M.C. Palazzo, E.V. Gurevich, V.V. Gurevich, Silent scaffolds: inhibition OF c-Jun N-terminal kinase 3 activity in cell by dominant-negative arrestin-3 mutant. J. Biol. Chem. 287(23), 19653–19664 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  57. M.R. Ahmed, X. Zhan, X. Song, S. Kook, V.V. Gurevich, E.V. Gurevich, Ubiquitin ligase parkin promotes Mdm2-arrestin interaction but inhibits arrestin ubiquitination. Biochemistry 50, 3749–3763 (2011)

    CAS  PubMed  Google Scholar 

  58. V.V. Gurevich, E.V. Gurevich, Extensive shape shifting underlies functional versatility of arrestins. Curr. Opin. Cell Biol. 27, 1–9 (2014)

    CAS  PubMed  Google Scholar 

  59. C. Schubert, J.A. Hirsch, V.V. Gurevich, D.M. Engelman, P.B. Sigler, K.G. Fleming, Visual arrestin activity may be regulated by self-association. J. Biol. Chem. 274, 21186–21190 (1999)

    CAS  PubMed  Google Scholar 

  60. S.M. Hanson, S.A. Vishnivetskiy, W.L. Hubbell, V.V. Gurevich, Opposing effects of inositol hexakisphosphate on rod arrestin and arrestin2 self-association. Biochemistry 47, 1070–1075 (2008)

    CAS  PubMed  Google Scholar 

  61. S.A. Vishnivetskiy, Q. Chen, M.C. Palazzo, E.K. Brooks, C. Altenbach, T.M. Iverson, W.L. Hubbell, V.V. Gurevich, Engineering visual arrestin-1 with special functional characteristics. J. Biol. Chem. 288(17), 11741–11750 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Q. Chen, Y. Zhuo, P. Sharma, I. Perez, D.J. Francis, S. Chakravarthy, S.A. Vishnivetskiy, S. Berndt, S.M. Hanson, X. Zhan, E.K. Brooks, C. Altenbach, W.L. Hubbell, C.S. Klug, T.M. Iverson, V.V. Gurevich, An eight amino acid segment controls oligomerization and preferred conformation of the two non-visual arrestins. J. Mol. Biol. 433(4), 166790 (2021)

    CAS  PubMed  Google Scholar 

  63. S.K. Milano, Y.M. Kim, F.P. Stefano, J.L. Benovic, C. Brenner, Nonvisual arrestin oligomerization and cellular localization are regulated by inositol hexakisphosphate binding. J. Biol. Chem. 281, 9812–9823 (2006)

    CAS  PubMed  Google Scholar 

  64. Q. Chen, N.A. Perry, S.A. Vishnivetskiy, S. Berndt, N.C. Gilbert, Y. Zhuo, P.K. Singh, J. Tholen, M.D. Ohi, E.V. Gurevich, C.A. Brautigam, K.S. Klug, V.V. Gurevich, T.M. Iverson, Structural basis of arrestin-3 activation and signaling. Nat. Commun. 8(1), 1427 (2017)

    PubMed  PubMed Central  Google Scholar 

  65. S. Samaranayake, S.A. Vishnivetskiy, C.R. Shores, K.C. Thibeault, S. Kook, J. Chen, M.E. Burns, E.V. Gurevich, V.V. Gurevich, Biological role of arrestin-1 oligomerization. J. Neurosci. 40(42), 8055–8069 (2020)

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Y. Imamoto, K. Kojima, R. Maeda, Y. Shichida, T. Oka, Role of monomer/tetramer equilibrium of rod visual arrestin in the interaction with phosphorylated rhodopsin. Int. J. Mol. Sci. 24(5), 4963 (2023)

    CAS  PubMed  PubMed Central  Google Scholar 

  67. T.H. Bayburt, S.A. Vishnivetskiy, M. McLean, T. Morizumi, C.-C. Huang, J.J. Tesmer, O.P. Ernst, S.G. Sligar, V.V. Gurevich, Rhodopsin monomer is sufficient for normal rhodopsin kinase (GRK1) phosphorylation and arrestin-1 binding. J. Biol. Chem. 286, 1420–1428 (2011)

    CAS  PubMed  Google Scholar 

  68. S.M. Hanson, E.V. Gurevich, S.A. Vishnivetskiy, M.R. Ahmed, X. Song, V.V. Gurevich, Each rhodopsin molecule binds its own arrestin. Proc. Nat. Acad. Sci. USA 104, 3125–3128 (2007)

    CAS  PubMed  PubMed Central  Google Scholar 

  69. X.E. Zhou, Y. He, P.W. de Waal, X. Gao, Y. Kang, N. Van Eps, Y. Yin, K. Pal, D. Goswami, T.A. White, A. Barty, N.R. Latorraca, H.N. Chapman, W.L. Hubbell, R.O. Dror, R.C. Stevens, V. Cherezov, V.V. Gurevich, P.R. Griffin, O.P. Ernst, K. Melcher, H.E. Xu, Identification of phosphorylation codes for arrestin recruitment by G protein-coupled receptors. Cell 170(3), 457–469 (2017)

    CAS  PubMed  PubMed Central  Google Scholar 

  70. J. Bous, A. Fouillen, H. Orcel, S. Trapani, X. Cong, S. Fontanel, J. Saint-Paul, J. Lai-Kee-Him, S. Urbach, N. Sibille, R. Sounier, S. Granier, B. Mouillac, P. Bron, Structure of the vasopressin hormone-V2 receptor-β-arrestin1 ternary complex. Sci. Adv. 8(35), eabo7761 (2022)

    CAS  PubMed  Google Scholar 

  71. C. Cao, X. Barros-Álvarez, S. Zhang, K. Kim, M.A. Dämgen, O. Panova, C.M. Suomivuori, J.F. Fay, X. Zhong, B.E. Krumm, R.H. Gumpper, A.B. Seven, M.J. Robertson, N.J. Krogan, R. Hüttenhain, D.E. Nichols, R.O. Dror, G. Skiniotis, B.L. Roth, Signaling snapshots of a serotonin receptor activated by the prototypical psychedelic LSD. Neuron 110(19), 3154–3167 (2022)

    CAS  PubMed  PubMed Central  Google Scholar 

  72. W. Huang, M. Masureel, Q. Qianhui, J. Janetzko, A. Inoue, H.E. Kato, M.J. Robertson, K.C. Nguyen, J.S. Glenn, G. Skiniotis, B.K. Kobilka, Structure of the neurotensin receptor 1 in complex with β-arrestin 1. Nature 579(7798), 303–308 (2020)

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Y. Lee, T. Warne, R. Nehmé, S. Pandey, H. Dwivedi-Agnihotri, M. Chaturvedi, P.C. Edwards, J. García-Nafría, A.G.W. Leslie, A.K. Shukla, C.G. Tate, Molecular basis of β-arrestin coupling to formoterol-bound β(1)-adrenoceptor. Nature 583(7818), 862–866 (2020)

    CAS  PubMed  PubMed Central  Google Scholar 

  74. D.P. Staus, H. Hu, M.J. Robertson, A.L.W. Kleinhenz, L.M. Wingler, W.D. Capel, N.R. Latorraca, R.J. Lefkowitz, G. Skiniotis, Structure of the M2 muscarinic receptor-β-arrestin complex in a lipid nanodisc. Nature 579(7798), 297–302 (2020)

    CAS  PubMed  PubMed Central  Google Scholar 

  75. W. Yin, Z. Li, M. Jin, Y.L. Yin, P.W. de Waal, K. Pal, Y. Yin, X. Gao, Y. He, J. Gao, X. Wang, Y. Zhang, H. Zhou, K. Melcher, Y. Jiang, Y. Cong, X. Edward Zhou, X. Yu, Xu. Eric, A complex structure of arrestin-2 bound to a G protein-coupled receptor. Cell Res. 29(12), 971–983 (2019)

    CAS  PubMed  PubMed Central  Google Scholar 

  76. A. Schleicher, H. Kuhn, K.P. Hofmann, Kinetics, binding constant, and activation energy of the 48-kDa protein-rhodopsin complex by extra-metarhodopsin II. Biochemistry 28(4), 1770–1775 (1989)

    CAS  PubMed  Google Scholar 

  77. K. Palczewski, J. Buczyłko, N.R. Imami, J.H. McDowell, P.A. Hargrave, Role of the carboxyl-terminal region of arrestin in binding to phosphorylated rhodopsin. J. Biol. Chem. 266, 15334–15339 (1991)

    CAS  PubMed  Google Scholar 

  78. V.V. Gurevich, S.M. Hanson, X. Song, S.A. Vishnivetskiy, E.V. Gurevich, The functional cycle of visual arrestins in photoreceptor cells. Prog. Retin. Eye Res. 30(6), 405–430 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  79. V.V. Gurevich, J.L. Benovic, Visual arrestin binding to rhodopsin: diverse functional roles of positively charged residues within the phosphorylation-recognition region of arrestin. J. Biol. Chem. 270(11), 6010–6016 (1995)

    CAS  PubMed  Google Scholar 

  80. V.V. Gurevich, The selectivity of visual arrestin for light-activated phosphorhodopsin is controlled by multiple nonredundant mechanisms. J. Biol. Chem. 273, 15501–15506 (1998)

    CAS  PubMed  Google Scholar 

  81. W.B. Asher, D.S. Terry, G.G.A. Gregorio, A.W. Kahsai, A. Borgia, B. Xie, A. Modak, Y. Zhu, W. Jang, A. Govindaraju, L.Y. Huang, A. Inoue, N.A. Lambert, V.V. Gurevich, L. Shi, R.J. Lefkowitz, S.C. Blanchard, J.A. Javitch, GPCR-mediated β-arrestin activation deconvoluted with single-molecule precision. Cell 185(10), 1661–1675 (2022)

    CAS  PubMed  PubMed Central  Google Scholar 

  82. A.K. Shukla, A. Manglik, A.C. Kruse, K. Xiao, R.I. Reis, W.C. Tseng, D.P. Staus, D. Hilger, S. Uysal, L.Y. Huang, M. Paduch, P. Tripathi-Shukla, A. Koide, S. Koide, W.I. Weis, A.A. Kossiakoff, B.K. Kobilka, R.J. Lefkowitz, Structure of active β-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide. Nature 497(7447), 137–141 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Y. Aydin, T. Böttke, J.H. Lam, S. Ernicke, A. Fortmann, M. Tretbar, B. Zarzycka, V.V. Gurevich, V. Katritch, I. Coin, Structural details of a class B GPCR-arrestin complex revealed by genetically encoded crosslinkers in living cells. Nat. Commun. 14(1), 1151 (2023)

    CAS  PubMed  PubMed Central  Google Scholar 

  84. J.A. Ballesteros, H. Weinstein, Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors. Methods Neurosci. 25, 366–428 (1995)

    CAS  Google Scholar 

  85. J. Kim, S. Ahn, X.R. Ren, E.J. Whalen, E. Reiter, H. Wei, R.J. Lefkowitz, Functional antagonism of different G protein-coupled receptor kinases for beta-arrestin-mediated angiotensin II receptor signaling. Proc. Nat. Acad. Sci. USA 102, 1442–1447 (2005)

    CAS  PubMed  PubMed Central  Google Scholar 

  86. K.N. Nobles, K. Xiao, S. Ahn, A.K. Shukla, C.M. Lam, S. Rajagopal, R.T. Strachan, T.Y. Huang, E.A. Bressler, M.R. Hara, S.K. Shenoy, S.P. Gygi, R.J. Lefkowitz, Distinct phosphorylation sites on the {beta}2-adrenergic receptor establish a barcode that encodes differential functions of {beta}-arrestin. Sci. Signal 4, 51 (2011)

    Google Scholar 

  87. M. Choi, D.P. Staus, L.M. Wingler, S. Ahn, B. Pani, W.D. Capel, R.J. Lefkowitz, G protein-coupled receptor kinases (GRKs) orchestrate biased agonism at the β2-adrenergic receptor. Sci. Signal 11, 544 (2018)

    Google Scholar 

  88. A.I. Kaya, N.A. Perry, V.V. Gurevich, T.M. Iverson, Phosphorylation barcode-dependent signal bias of the dopamine D1 receptor. Proc. Nat. Acad. Sci. USA 117(25), 14139–14149 (2020)

    CAS  PubMed  PubMed Central  Google Scholar 

  89. X.R. Ren, E. Reiter, S. Ahn, J. Kim, W. Chen, R.J. Lefkowitz, Different G protein-coupled receptor kinases govern G protein and beta-arrestin mediated signaling of V2 vasopressin receptor. Proc. Nat. Acad. Sci. USA 102, 1448–1453 (2005)

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by NIH Grants EY011500, GM122491, and Cornelius Vanderbilt Endowed Chair (Vanderbilt University).

Funding

Supported in part by NIH RO1 EY011500, R35 GM122491, and Cornelius Vanderbilt Endowed Chair (Vanderbilt University).

Author information

Authors and Affiliations

  1. Department of Pharmacology, Department of Pharmacology, Vanderbilt University, 2200 Pierce Ave South, PRB, Rm. 417D, Nashville, TN, 37232, USA

    Vsevolod V. Gurevich & Eugenia V. Gurevich

Authors
  1. Vsevolod V. Gurevich
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eugenia V. Gurevich
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

VVG wrote and edited the manuscript. EVG edited the manuscript and created figures.

Corresponding author

Correspondence to Vsevolod V. Gurevich.

Ethics declarations

Conflict of Interests

The authors declare no competing interests.

Ethical approval

No human or animal studies.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The original online version of this article was revised as the second author’s name Eugenia V. Gurevich was incorrectly written as Eugenis V. Gurevich.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gurevich, V.V., Gurevich, E.V. Dynamic Nature of Proteins is Critically Important for Their Function: GPCRs and Signal Transducers. Appl Magn Reson 55, 11–25 (2024). https://doi.org/10.1007/s00723-023-01561-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00723-023-01561-8

Search

Navigation