Luis Eduardo Diaz Gimenez, PhD
Post-doctoral fellow, Pharmacology
MD 1990 – 1997 Lisandro Alvarado Center-West University, Bar-quisimeto, Venezuela.
PhD (Cellular Biology) 1997 – 2003 Federal University of Rio de Janeiro, Brazil
Luis worked in the lab 2008-2014. Different mammalian species express ~800-3,200 GPCR subtypes, but only four arrestin proteins, two of which (arrestin-1 and arrestin-4, a.k.a. rod and cone arrestins) are selectively expressed in photoreceptor cells. This leaves just two non-visual subtypes, arrestin-2 and arrestin-3 (a.k.a. b-arrestin1 and b-arrestin2, respectively) to “serve” all other GPCRs. Therefore, it is not surprising that wild type arrestin-2 and -3 are quite promiscuous. In contrast, arrestin-1 demonstrates high specificity for just one receptor, rhodopsin. Using a series of arrestin-1/2 chimeras we earlier identified arrestin elements responsible for receptor preference. Subsequent targeted mutagenesis identified ten residues that are largely responsible for receptor specificity of arrestin proteins. Based on these data and the analysis of arrestin evolution, we designed mutant arrestins that we expected to have significantly enhanced preference for groups of receptors and individual subtypes. Using BRET-based in-cell assays, Luis showed that these mutations enhance receptor preference, and that combinations of several mutations act additively. This work yielded versions of naturally promiscuous arrestin-3 with >50-fold preference for some receptors over others.
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 in press (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).
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).
Breitman, M., Kook, S., Gimenez, L.E., Lizama, B.N., Palazzo, M.C., Gurevich, E.V., Gurevich, V.V. 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, 19653-19664 (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).
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).
Zhan, X., Gimenez, L.E., Gurevich, V.V., Spiller B.W. Crystal structure of arrestin-3 reveals the basis of the difference in receptor binding between two non-visual subtypes. J Mol Biol 406, 467-478 (2011).
Walther, C., Nagel, S., Gimenez, L.E., Morl, K., Gurevich, V.V., Beck-Sickinger, A.G. Ligand induced internalization and recycling of the human neuropeptide Y2 receptor is regulated by its C-terminal tail. J Biol Chem 285, 41578-41590 (2010).