J 2021

Cysteine Modification by Ebselen Reduces the Stability and Cellular Levels of 14-3-3 Proteins

WALØEN, Kai, Kunwar JUNG-KC, Elisa D. VECCHIA, Sunil PANDEY, Norbert GAŠPARIK et. al.

Základní údaje

Originální název

Cysteine Modification by Ebselen Reduces the Stability and Cellular Levels of 14-3-3 Proteins

Autoři

WALØEN, Kai, Kunwar JUNG-KC, Elisa D. VECCHIA, Sunil PANDEY, Norbert GAŠPARIK (703 Slovensko, domácí), Anne DØSKELAND, Sudarshan PATIL, Rune KLEPPE, Jozef HRITZ (703 Slovensko, domácí), William H J NORTON, Aurora MARTINEZ a Jan HAAVIK (garant)

Vydání

Molecular Pharmacology, American Society for Pharmacology and Experimental Therapeutics, 2021, 0026-895X

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10608 Biochemistry and molecular biology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

Impakt faktor

Impact factor: 4.054

Kód RIV

RIV/00216224:14740/21:00119210

Organizační jednotka

Středoevropský technologický institut

DOI

UT WoS

000752482400001

Klíčová slova anglicky

TYROSINE-HYDROXYLASE; STRUCTURAL BASIS; PHOSPHORYLATION; 14-3-3-PROTEINS; IDENTIFICATION; PROLIFERATION; THIMEROSAL; INHIBITOR; OXIDATION; TARGETS

Štítky

Příznaky

Mezinárodní význam, Recenzováno
Změněno: 2. 11. 2024 20:50, Ing. Martina Blahová

Anotace

V originále

The 14-3-3 proteins constitute a family of adaptor proteins with many binding partners and biological functions, and they are considered promising drug targets in cancer and neuropsychiatry. By screening 1280 small-molecule drugs using differential scanning fluorimetry (DSF), we found 15 compounds that decreased the thermal stability of 14-3-3ζ. Among these compounds, ebselen was identified as a covalent, destabilizing ligand of 14-3-3 isoforms ζ, ε, γ, and η. Ebselen bonding decreased 14-3-3ζ binding to its partner Ser19-phosphorylated tyrosine hydroxylase. Characterization of site-directed mutants at cysteine residues in 14-3-3ζ (C25, C94, and C189) by DSF and mass spectroscopy revealed covalent modification by ebselen of all cysteines through a selenylsulfide bond. C25 appeared to be the preferential site of ebselen interaction in vitro, whereas modification of C94 was the main determinant for protein destabilization. At therapeutically relevant concentrations, ebselen and ebselen oxide caused decreased 14-3-3 levels in SH-SY5Y cells, accompanied with an increased degradation, most probably by the ubiquitin-dependent proteasome pathway. Moreover, ebselen-treated zebrafish displayed decreased brain 14-3-3 content, a freezing phenotype, and reduced mobility, resembling the effects of lithium, consistent with its proposed action as a safer lithium-mimetic drug. Ebselen has recently emerged as a promising drug candidate in several medical areas, such as cancer, neuropsychiatric disorders, and infectious diseases, including coronavirus disease 2019. Its pleiotropic actions are attributed to antioxidant effects and formation of selenosulfides with critical cysteine residues in proteins. Our work indicates that a destabilization of 14-3-3 may affect the protein interaction networks of this protein family, contributing to the therapeutic potential of ebselen.

Návaznosti

EF16_013/0001776, projekt VaV
Název: Česká infrastruktura pro integrativní strukturní biologii pro lidské zdraví
GF20-05789L, projekt VaV
Název: Charakterizace přirozeně neuspořádaných proteinů
Investor: Grantová agentura ČR, Characterization of intrinsically disordered proteins, Partnerská agentura (Rakousko)
90127, velká výzkumná infrastruktura
Název: CIISB II