The sequence [EKRKI(E/R)(K/L/R/S/T)] is a nuclear localization signal for importin 7 binding (NLS7)

Panagiotopoulos, Athanasios A.; Polioudaki, Chara; Ntallis, Sotirios G; Dellis, Dimitris; Notas, George; Panagiotidis, Christos Α.; Theodoropoulos, Panayiotis A.; Castanas, Elias; Kampa, Marilena

doi:10.1016/j.bbagen.2021.129851

Cited by 14 publications

(16 citation statements)

References 86 publications

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“…Because of these data, we attempted an in silico modeling of a putative molecular interaction of these findings. Our simulation, both for unliganded and E2-liganded receptors, was based on the following: (a) the identification of the prototype NLS sequence on each molecule was detected [ 25 ], permitting the interaction of each protein with the karyopherin α complex; (b) special attention was paid to the position of the Nuclear Localization Signal (NLS) of each molecule, the site of the interaction of each complex with the hetero-protein importin α-importin β–Ran–GDP [ 26 ]; (c) we modeled the whole length of ERα36. We are aware that the presence of unstructured regions in the receptor might have made this “expanded” model of ERα36 monomer and dimer not completely accurate.…”

Section: Resultsmentioning

confidence: 99%

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ERα36–GPER1 Collaboration Inhibits TLR4/NFκB-Induced Pro-Inflammatory Activity in Breast Cancer Cells

Notas

Panagiotopoulos

Vamvoukaki

et al. 2021

IJMS

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Inflammation is important for the initiation and progression of breast cancer. We have previously reported that in monocytes, estrogen regulates TLR4/NFκB-mediated inflammation via the interaction of the Erα isoform ERα36 with GPER1. We therefore investigated whether a similar mechanism is present in breast cancer epithelial cells, and the effect of ERα36 expression on the classic 66 kD ERα isoform (ERα66) functions. We report that estrogen inhibits LPS-induced NFκB activity and the expression of downstream molecules TNFα and IL-6. In the absence of ERα66, ERα36 and GPER1 are both indispensable for this effect. In the presence of ERα66, ERα36 or GPER1 knock-down partially inhibits NFκB-mediated inflammation. In both cases, ERα36 overexpression enhances the inhibitory effect of estrogen on inflammation. We also verify that ERα36 and GPER1 physically interact, especially after LPS treatment, and that GPER1 interacts directly with NFκB. When both ERα66 and ERα36 are expressed, the latter acts as an inhibitor of ERα66 via its binding to estrogen response elements. We also report that the activation of ERα36 leads to the inhibition of breast cancer cell proliferation. Our data support that ERα36 is an inhibitory estrogen receptor that, in collaboration with GPER1, inhibits NFκB-mediated inflammation and ERα66 actions in breast cancer cells.

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Section: Resultsmentioning

confidence: 99%

“…The in silico experimental procedure was described in detail in a recent work [25]. Briefly, the sequences of receptors and NFκB p65 molecules (in Fasta format) were retrieved from the NCBI gene database (https://www.ncbi.nlm.nih.gov/gene/, accessed on 3 May 2019).…”

Section: Molecular Modelingmentioning

confidence: 99%

ERα36–GPER1 Collaboration Inhibits TLR4/NFκB-Induced Pro-Inflammatory Activity in Breast Cancer Cells

Notas

Panagiotopoulos

Vamvoukaki

et al. 2021

IJMS

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“…Simulation of N binding with the complex IMPα-IMPβ-RanGDP and viral RNA (see Ref. [35] for methodological details) (Figure 1B) confirmed the highaffinity binding of Importin complex to N (ΔG −1000.5 kcal/mol for importins and −418.7 kcal/mol for RNA, localized at the structured Nterminal part of the protein, Figure 1B). Previous reports suggest that SARS-CoV-2 protein dimerizes through an interaction of its N-CTD η1 domain.…”

Section: In Silico Simulation Reveals That P-cymene Interacts With the Importin-binding Domain Of Sars-cov-2 N Protein And Impairs Its Asmentioning

confidence: 64%

“…The crystal structure of the SARS‐CoV‐2 nucleocapsid protein (C‐terminal dimerization domain, residues 249–389, PDB entry: 6WJI 28 ) and human importin‐α (residues 71–197) containing the interaction site with the NLS sequence of cargo proteins 35 were used as initial coordinates to build MD models. A nucleocapsid–importin complex was produced based on docking calculations with the HEX 34 program.…”

Section: Methodsmentioning

confidence: 99%

“…19 Therefore, we have scanned the SARS-CoV-2 N protein for the existence of the prototype NLSα sequence PRQKRTATKAY. 35 It was identified in position 258-268 of the N protein, within its structured C-terminal part (Figure 1A). Simulation of N binding with the complex IMPα-IMPβ-RanGDP and viral RNA (see Ref.…”

Section: In Silico Simulation Reveals That P-cymene Interacts With the Importin-binding Domain Of Sars-cov-2 N Protein And Impairs Its Asmentioning

confidence: 99%

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p‐cymene impairs SARS‐CoV‐2 and Influenza A (H1N1) viral replication: In silico predicted interaction with SARS‐CoV‐2 nucleocapsid protein and H1N1 nucleoprotein

Panagiotopoulos

Tseliou

Karakasiliotis

et al. 2021

Pharmacology Res & Perspec

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Therapeutic regimens for the COVID‐19 pandemics remain unmet. In this line, repurposing of existing drugs against known or predicted SARS‐CoV‐2 protein actions have been advanced, while natural products have also been tested. Here, we propose that p‐cymene, a natural monoterpene, can act as a potential novel agent for the treatment of SARS‐CoV‐2‐induced COVID‐19 and other RNA‐virus‐induced diseases (influenza, rabies, Ebola). We show by extensive molecular simulations that SARS‐CoV‐2 C‐terminal structured domain contains a nuclear localization signal (NLS), like SARS‐CoV, on which p‐cymene binds with low micromolar affinity, impairing nuclear translocation of this protein and inhibiting viral replication, as verified by preliminary in vitro experiments. A similar mechanism may occur in other RNA‐viruses (influenza, rabies and Ebola), also verified in vitro for influenza, by interaction of p‐cymene with viral nucleoproteins, and structural modification of their NLS site, weakening its interaction with importin A. This common mechanism of action renders therefore p‐cymene as a possible antiviral, alone, or in combination with other agents, in a broad spectrum of RNA viruses, from SARS‐CoV‐2 to influenza A infections.

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Recognition motifs for importin 4 [(L)PPRS(G/P)P] and importin 5 [KP(K/Y)LV] binding, identified by bio-informatic simulation and experimental in vitro validation

Panagiotopoulos

Kalyvianaki²,

Tsodoulou³

et al. 2022

Computational and Structural Biotechnology Journal

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The sequence [EKRKI(E/R)(K/L/R/S/T)] is a nuclear localization signal for importin 7 binding (NLS7)

Cited by 14 publications

References 86 publications

ERα36–GPER1 Collaboration Inhibits TLR4/NFκB-Induced Pro-Inflammatory Activity in Breast Cancer Cells

ERα36–GPER1 Collaboration Inhibits TLR4/NFκB-Induced Pro-Inflammatory Activity in Breast Cancer Cells

p‐cymene impairs SARS‐CoV‐2 and Influenza A (H1N1) viral replication: In silico predicted interaction with SARS‐CoV‐2 nucleocapsid protein and H1N1 nucleoprotein

Recognition motifs for importin 4 [(L)PPRS(G/P)P] and importin 5 [KP(K/Y)LV] binding, identified by bio-informatic simulation and experimental in vitro validation

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