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Sergey A. Vishnivetskiy, PhD

Research Assistant Professor, Pharmacology


Education:
Ph.D. Biochemistry Institute of Biochemistry& Physiology of Microorganisms, Russian Academy of Sciences 1992
B.Sc. M.Sc. Biochemistry Moscow State University 1986

Research Description

Sergey is performing structure-function studies of arrestin proteins. One of our goals is to elucidate the fine molecular mechanisms that govern the interaction of arrestins with their partners. Or, in plain English, we want to find out how arrestin knows when to bind the receptor and when to go away. These mechanistic studies involve site-directed mutagenesis, chimera construction, in vitro binding assays, protein expression and purification, X-ray crystallography, site-directed spin labeling/EPR, NMR, and various biochemical methods. These studies yield a great deal of information and generate mutants with unusual functional characteristics that we then use to investigate the biological function of arrestin proteins.

Sergey has constructed several structurally distinct variants of constitutively active arrestins that do not require receptor phosphorylation for high-affinity binding (i.e., they bind to any activated forms of the receptor, phosphorylated or not). Since excessive signaling by a variety of G protein-coupled receptors causes various congenital disorders ranging from night blindness and retinal degeneration to several forms of cancer, these “super-arrestins” may prove useful for gene therapy of these disorders. To this end, as a proof-of-principle experiment we made transgenic mice expressing phosphorylation-independent visual arrestin in photoreceptor cells. We bred the transgene into backgrounds where rhodopsin shutoff is defective due to lack of rhodopsin kinase or because they have mutant rhodopsin which does not have phosphorylation sites. We found that phosphorylation-independent arrestins prevent light-dependent retinal degeneration in these mice, improve functional performance of rod photoreceptors, and speed up signaling shutoff. Thus, compensational approach to gene therapy of gain-of-function receptor mutations works. However, the “compensated” rods did not perform as well as true WT rods. So, we are further redesigning visual arrestin-1 to create a mutant with even higher affinity for unphosphorylated active rhodopsin to achieve more complete compensation.

Sergey worked in the lab since 1998. As of December 28, 2021 he has 65 papers from the lab in Pubmed.

 

Publications (we publish a lot, so search Medline for an update):

Perry-Hauser, N.A., Hopkins, J.B., Zhuo, Y., Zheng, C., Perez, I., Schulz, K.M., Vishnivetskiy, S.A., Kaya, A.I., Sharma, P., Dalby, K.N., Chung, K.Y., Klug, C.S., Gurevich, V.V., Iverson, T.M. The two non-visual arrestins engage ERK2 differently. J Mol Biol 434, (7), 167465; doi: 10.1016/j.jmb.2022.167465 (2022).

Karnam, P., Vishnivetskiy, S.A., Gurevich, V.V. Structural basis of arrestin selectivity for active phosphorylated G protein-coupled receptors. Int J Mol Sci 22 (22), 12481; DOI: doi.org/10.3390/ijms222212481 (2021).

Perez, I., Berndt, S., Agarwal, R., Castro, M.A., Vishnivetskiy, S.A., Smith, J.C., Sanders, C.R., Gurevich, V.V., Iverson, T.M. A model of the signal initiation complex between arrestin-3 and the Src family kinase Fgr. J Mol Biol 434, 167400; doi: 10.1016/j.jmb.2021.167400 (2022)

Vishnivetskiy, S.A., Huh, E.K., Gurevich, E.V., Gurevich, V.V. The finger loop as an activation sensor in arrestin 157 (4), 1138-1152 ; doi: 10.1111/jnc.15232 (2021).

Vishnivetskiy, S.A., Zheng, C., May, M.B., Karnam, P.C., Gurevich, E.V., Gurevich, V.V. Lysine in the lariat loop of arrestin does not serve as phosphate sensor. J Neurochem 156, 435-444; doi: 10.1111/jnc.15110 (2021).

Chen, Q., Zhuo, Y., Sharma, P., Perez, I., Francis, D.J., Chakravarthy, S., Vishnivetskiy, S.A., Berndt, S., Hanson, S.M., Zhan, X., Brooks, E.K., Altenbach, C., Hubbell, W.L., Klug, C.S., Iverson, T.M., Gurevich, V.V. An eight amino acid segment controls oligomerization and preferred conformation of the two non-visual arrestins. J Mol Biol 433 (4), 166790; doi: 10.1016/j.jmb.2020.166790 (2021).

Zhuo, Y., Gurevich, V.V., Vishnivetskiy, S.A., Klug, C. Marchese, A. A non-GPCR binding partner interacts with a novel surface on β-arrestin1 to mediate GPCR signaling. J Biol Chem, in press; doi: 10.1074/jbc.RA120.015074 (2020).

Krug, U., Gloge, A., Schmidt, P., Baldus, J., Bernhard, F., Kaiser, A., Montag, C., Gauglitz, M., Vishnivetskiy, S.A., Gurevich, V.V., Beck-Sickinger, A.G., Glaubitz, C., Huster, D. The Conformational Equilibrium of the Neuropeptide Y2 Receptor. Angew Chem Int Ed Engl, in press; doi: 10.1002/anie.202006075 (2020).

Samaranayake, S., Vishnivetskiy, S.A., Shores, C.R., Thibeault, K.C., Kook, S.,Chen, J., Burns, M.E., Gurevich, E.V., Gurevich, V.V. Biological role of arrestin-1 oligomerization. J Neurosci, in press (2020).

Meister, J., Bone, D.B.J., Godlewski, G., Liu, Z., Lee, R.J., Vishnivetskiy, S.A., Gurevich, V.V., Springe,r D., Kunos, G., Wess, J. Metabolic effects of skeletal muscle-specific deletion of beta-arrestin-1 and -2 in mice. PLoS Genet. 2019 Oct 17;15(10) e1008424, doi: 10.1371/journal.pgen.1008424 (2019).

Kook, S., Vishnivetskiy, S.A., Gurevich, V.V., Gurevich, E.V. Cleavage of arrestin-3 by caspases attenuates cell death by precluding arrestin-dependent JNK activation. Cell Signal, in press (2019).

Samaranayake, S., Song, X., Vishnivetskiy, S.A., Chen, J., Gurevich, E.V., Gurevich, V.V. Enhanced mutant compensates for defects in rhodopsin phosphorylation in the presence of endogenous arrestin-1. Front Mol Neurosci 11, 203; doi: 10.3389/fnmol.2018.00203 (2018)

Tso, S.-C., Chen, Q., Vishnivetskiy, S.A., Gurevich, V.V., Iverson T.M., Brautigam, C.A. Using two-site binding models to analyze microscale thermophoresis data. Anal Biochem 540-541, 64-75; doi: 10.1016/j.ab.2017.10.013 (2018).

Vishnivetskiy, S.A., Sullivan, L.S., Bowne, S.J., Daiger, S.P., Gurevich, E.V., Gurevich, V.V. Molecular defects of the disease-causing human arrestin-1 C147F mutants. IInvest Ophthalmol Vis Sci 59 (1), 13-20; doi: 10.1167/iovs.17-22180 (2018).

Chen, Q., Perry, N.A., Vishnivetskiy, S.A., Berndt, S., Gilbert, N.C., Zhuo, Y., Singh, P.K., Tholen, J., Ohi, M.D., Gurevich, E.V., Brautigam, C.A., Klug, C.S., Gurevich, V.V., Iverson, T.M. Structural basis of arrestin-3 activation and signaling. Nat Commun 8, 1427; doi: 10.1038/s41467-01701218-8 (2017).

Vishnivetskiy, S.A., Lee, R.J., Zhou, X.E., Franz, A., Xu, Q., Xu, H.E., Gurevich, V.V. Functional role of the three conserved cysteines in the N-domain of visual arrestin-1. J Biol Chem, 292 (30), 12496-12502; doi: 10.1074/jbc.M117.790386 (2017).

Vishnivetskiy, S.A., Hubbell, W.L., Klug, C.S., Gurevich, V.V. GPCR footprint on arrestins and manipulation of receptor specificity. Ch 10 in The structural basis of arrestin functions. Springer-Verlag, Berlin-Heidelberg, ISBN 978-3-319-57552-0 (2017).

Wiener, R, Vishnivetskiy, S.A., Gurevich, V.V., Hirsch, J.A. Phosphate sensor and construction of phosphorylation-independent arrestins. Ch 6 in The structural basis of arrestin functions. Springer-Verlag, Berlin-Heidelberg, ISBN 978-3-319-57552-0 (2017).

Inagaki, S., Ghirlando, R., Vishnivetskiy, S.A., Homan, K.T., White, J.F., Tesmer, J.J., Gurevich, V.V., Grisshammer, R. G protein-coupled receptor kinase 2 (GRK2) and 5 (GRK5) exhibit selective phosphorylation of the neurotensin receptor in vitro. Biochemistry 54 (28), 4320-9 (2015).

Kang, Y., Zhou, X.E., Gao, X., He, Y., Liu, W., Ishchenko, A., Barty, A., White, T.A., Yefanov, O., Han, G.W., Xu, Q., de Waal, P.W., Ke, J., Tan, M.H.E., Zhang, C., Moeller, A., West, G.M., Van Eps, N., Caro, L.N., Vishnivetskiy, S.A., Lee, R.J., Suino-Powell, K.M., Gu, X., Pal, K., Ma, J., Zhi, X., Boutet, S., Williams, G.J., Messerschmidt, M., Gati, C., Zatsepin, N.A., Wang, D., James, D., Basu, S., Roy-Chowdhury, S., Conrad, C., Coe, J., Liu, H., Lisova, S., Kupitz, C., Grotjohnn, I., Fromme, R., Jiang, Y., Tasn, M., Yang, H., Li, J., Wang, M., Li, D., Zhao, Y., Standfuss, J., Diederichs, K., Potter, C.S., Carragher, B., Caffrey, M., Jiang, H., Chapman, H.N., Spence, J.C.H., Fromme, P., Weierstall, U., Ernst, O.P., Gurevich, V.V., Griffin, P.R., Hubbell, W.L., Stevens, R.C., Cherezov, V., Melcher, K., Xu, H.E. Crystal structure of rhodopsin bound to arrestin determined by femtosecond X-ray laser. Nature, 523( 7562):561-7. doi: 10.1038/nature14656 (2025).

Azevedo, A.W., Doan, T., Moaven, H., Sokal, I., Baameur, F., Vishnivetskiy, S.A., Homan, K.T., Tesmer, J.J.G., Gurevich, V.V., Chen, J., Rieke, F. C-terminal Threonines and Serines Play Distinct Roles in the Desensitization of Rhodopsin, a G protein-Coupled Receptor. eLife 4: e05981 doi: 10.7554/eLife.05981 (2015).

Li, L., Homan, K.T., Vishnivetskiy S.A., Manglik, A., Tesmer, J.J., Gurevich, V.V., Gurevich, E.V. G ptotein-coupled receptor kinases of the GRK4 protein subfamily phosphorylate inactive G protein-coupled receptors (GPCRs). J Biol Chem 290 (17), 10775-10790 (2015).

Vishnivetskiy S.A., Zhan, X., Chen, Q., Iverson, T.M., Gurevich VV. Arrestin expression in E. coli and purification. Curr Protoc Pharmacol 67, 2.11.1-2.11.19 (2014).

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

Zhan, X., Perez, A., Gimenez, L.E., Vishnivetskiy, S.A., Gurevich, V.V. Arrestin-3 binds the MAP kinase JNK3a2 via multiple sites on both domains. Cell Signal 26 (4), 766-776 (2014).

Gurevich, V.V., Song, X., Visnivetskiy, S.A., Gurevich, E.V. Enhanced phosphorylation-independent arrestins and gene therapy. In: Arrestins – Pharmacology and Therapeutic Potential. Handb Exp Pharmacol 219, p. 133-152, Springer-Verlag, Berlin-Heidelberg (2014).

Gimenez, L.E., Vishnivetskiy, S.A., and Gurevich, V.V.  Targeting individual GPCRs with redesigned non-visual arrestins. In: Arrestins – Pharmacology and Therapeutic Potential. Handb Exp Pharmacol 219, p. 153-170, Springer-Verlag, Berlin-Heidelberg (2014).

Chen, Q., Zhuo, Y., Kim, M., Hanson, S.M., Vishnivetskiy, S.A., Altenbach, C., Klug, C.S., Hubbell, W.L., and Gurevich, V.V. Self-association of arrestin family members. In: Arrestins – Pharmacology and Therapeutic Potential. Handb Exp Pharmacol 219, p. 205-223, Springer-Verlag, Berlin-Heidelberg (2014).

Song, X., Seo, J., Baameur, F., Vishnivetskiy, S.A., Chen, Q., Kook, S., Kim, M., Brooks, E.K., Altenbach, C., Hong, Y., Hanson, S.M., Palazzo, M.C., Chen, J., Hubbell, W.L., Gurevich, E.V., Gurevich, V.V. Rapid degeneration of rod photoreceptors expressing self-association-deficient arrestin-1 mutant. Cell Signal 25, 2613-2624 (2013).

Vishnivetskiy, S.A., Ostermaier, M.K., Singhal, A., Panneels, V., Homan, K.T., Glukhova, A., Sligar, S.G., Tesmer, J.J.G., Schertler, G.F.X., Standfuss, J., Gurevich, V.V. Constitutively active rhodopsin mutants causing night blindness are effectively phosphorylated by GRKs but differ in arrestin-1 binding. Cell Signal 25 (11), 2155-2162 (2013).

Vishnivetskiy, S.A., Baameur, F., Findley, K.R., Gurevich, V.V. Critical role of central 139-loop in stability and binding selectivity of arrestin-1. J Biol Chem 288 (17), 11741-50 (2013).

Singhal, A., Ostermaier, M.K., Vishnivetskiy, S.A., Panneels, V., Homan, K.T., Tesmer, J.J.G., Veprintsev, D., Deupi, X., Gurevich, V.V., Schertler, G.F.X., Standfuss, J. Insights into congenital stationary night blindness based on the structure of G90D rhodopsin. EMBO Rep 14 (6), 520-526 (2013).

Vishnivetskiy, S.A., Chen, Q., Palazzo, M.C., Brooks, E.K., Altenbach, C., Iverson, T.M., Hubbell, W.L., Gurevich, V.V. Engineering visual arrestin-1 with special functional characteristics. J Biol Chem 288 (5), 3394-3405 (2013).

Zhuang, T., Chen, Q., Cho, M.-K., Vishnivetskiy, S.A., Iverson, T.M., Gurevich*, V.V., Sanders*, C.R. (*corresponding authors). Involvement of distinct arrestin-1 elements in binding to different functional forms of rhodopsin. Proc. Natl. Acad. Sci. USA 110 (3), 942-947 (2013).

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

Gimenez, L.E., Vishnivetskiy, S.A., Baameur, F., Gurevich, V.V. Manipulation of very few receptor-dicriminator residues greatly enhances receptor specificity of non-visual arrestins. J Biol Chem 287, 29495-29505 (2012).

Gimenez, L.E., Kook, S., Vishnivetskiy, S.A., Ahmed, M.R., Gurevich, E.V., Gurevich, V.V. The role of receptor-attached phosphates in the binding of visual and non-visual arrestins to G protein-coupled receptors. J Biol Chem 287, 9028-9040 (2012)

Cleghorn, W.M., Tsakem, E.L., Song, X., Vishnivetskiy, S.A., Seo, J., Chen, J., Gurevich, E.V., andGurevich, V.V. Progressive reduction of its expression in rods reveales two pools of arrestin-1 in the outer segment with different roles in photoresponse recovery. PLoS One 6 (7), e22797 (2011)

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

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

Song, X., Vishnivetskiy, S.A., Seo, J., Chen, J., Gurevich, E.V., Gurevich, V.V. Arrestin-1 expression level in rods: balancing functional performance and photoreceptor health. Neuroscience 174, 37-49 (2011)

Bayburt, T.H., Vishnivetskiy, S.A., McLean, M.A., Morizumi, T., Huang, C.-c., Tesmer, J.J.G., Ernst, O.P., Sligar, S.G., Gurevich, V.V. Monomeric rhodopsin is sufficient for normal rhodopsin kinase (GRK1) phosphorylation and arrestin-1 binding. J Biol Chem 286, 1420-8 (2011).

Zhuang, T., Vishnivetskiy, S.A., Gurevich, V.V., Sanders, C.R. Elucidation of IP6 and heparin interaction site and conformational changes in arrestin-1 by solution NMR. Biochemistry 49, 10473-10485 (2010)

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

Song, X., Vishnivetskiy, S.A., Gross, O.P., Emelianoff, K., Mendez, A., Chen, J.,  Gurevich, E.V., Burns, M.E., Gurevich, V.V. Enhanced arrestin facilitates recovery and protects rods lacking rhodopsin phosphorylation Curr Biol 19, 700-705 (2009).

Hanson, S.M., Vishnivetskiy, S.A., Hubbell, W.L., and Gurevich, V.V. The opposing effects of inositol hexakisphosphate (IP6) on rod arrestin and arrestin2 self-association. Biochemistry 47, 1070-5 (2008).

Vishnivetskiy, S.A., Raman, D., Wei, J., Kennedy, M.J., Hurley, J.B., Gurevich, V.V. Regulation of arrestin binding by rhodopsin phosphorylation level. J Biol Chem 282, 32075-83 (2007).

Gurevich, V.V., Hanson, S.M., Gurevich, E.V., Vishnivetskiy, S.A. How Rod Arrestin Achieved Perfection: Regulation of its Availability and Binding Selectivity. In: Signal Transduction in the retina (Kisselev, O., and Fliesler, S.J., Eds), pp 55-88. Methods in Signal Transduction Series, CRC Press, Boca Raton, FL (2007).

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

Hanson, S.M., Van Eps, N., Francis, D.J., Altenbach, C., Vishnivetskiy, S.A., Arshavsky, V.Y., Klug, C.S., Hubbell, W.L., and Gurevich, V.V. Structure and Function of the Visual Arrestin Oligomer. EMBO J 26 , 1726-36 (2007).

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

Wu, N., Macion-Dazard, R., Nithianantham, S., Xu, Z., Hanson, S.M., Vishnivetskiy, S.A., Gurevich, V.V., Thibonnier, M., and Shoham, M. Soluble mimics of the cytoplasmic face of the human V1-vascular vasopressin receptor bind arrestin2 and calmodulin. Mol Pharmacol 70, 249-258 (2006).

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

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

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

Nair, K.S., Hanson, S.M., Mendez, A., Gurevich, E.V., Kennedy, M.J., Shestopalov, V.I.,  Vishnivetskiy, S.A., Chen, J., Hurley, J.B., Gurevich, V.V., and Slepak, V.Z. Light-dependent re-distribution of arrestin in vertebrate rods is an energy-independent process governed by protein-protein interactions.Neuron 46, 555-567 (2005).

Vishnivetskiy, S.A., Hosey, M.M., Benovic, J.L., Gurevich, V.V.  Mapping the arrestin-receptor interface: Structural elements responsible for receptor specificity of arrestin proteins.
J BIOL CHEM   279(2):1262-1268 JAN  9 2004

Vishnivetskiy, S.A., Hirsch, J.A., Velez, M.G.,  Gurevich, Y.V., Gurevich, V.V. Transition of arrestin into the active receptor-binding state requires an extended interdomain hinge. J BIOL CHEM 277 (46): 43961-43967 NOV 15 2002

Celver, J., Vishnivetskiy, S.A., Chavkin, C., and Gurevich, V.V. Conservation of the phosphate-sensitive elements in the arrestin family of proteins. J BIOL CHEM 277 (11):9043-9048 MAR 15 2002

Han, M., Gurevich, V.V., Vishnivetskiy, S.A., Sigler, P.B., Schubert, C. Crystal structure of beta-arrestin at 1.9 angstrom: Possible mechanism of receptor binding and membrane translocation. STRUCTURE (Camb) 9 (9): 869-880 SEP 2001

Vishnivetskiy, S.A., Schubert, C., Climaco, G.C., Gurevich, Y.V., Gurevich, V.V. An additional phosphate-binding element in arrestin molecule – Implications for the mechanism of arrestin activation. J BIOL CHEM 275 (52): 41049-41057 DEC 29 2000

Smith, W.C., Gurevich, E.V., Dugger, D.R., Shelamer, C.L., Vishnivetskiy, S.A., McDowell, H., and Gurevich, V.V. Cloning and functional characterization of salamander rod and cone arrestins. INVEST OPHTH VIS SCI 41 (9): 2445-2455 AUG 2000

Mushegian, A.R., Vishnivetskiy, S.A., and Gurevich, V.V. Conserved phosphoprotein interaction motif is functionally interchangeable between ataxin-7 and arrestins. BIOCHEMISTRY-US 39 (23): 6809-6813 JUN 13 2000

Vishnivetskiy, S.A., Paz, C.L., Schubert, C., Hirsch, J.A., Sigler, P.B., and Gurevich, V.V. How does arrestin respond to the phosphorylated state of rhodopsin? J BIOL CHEM 274 (17): 11451-11454 APR 23 1999