Sleep deprivation changes thimet oligopeptidase (THOP1) expression and activity in rat brain

Visniauskas, Bruna; Simões, Priscila Santos Rodrigues; Dalio, Fernanda M.; Naffah-Mazzacoratti, Maria da Graça; Oliveira, Vitor; Tufik, Sérgio; Chagas, Jair Ribeiro

doi:10.1016/j.heliyon.2019.e02896

Cited by 3 publications

(5 citation statements)

References 59 publications

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“…Furthermore, THOP1 appears to play a crucial role in the regulation of MHC I cell-surface expression [ 101 – 103 ]. Due to the shown high expression of THOP1 in several brain compartments and in the effector CD8 T-cells of COVID-19 patients [ 100 ], it raises the question about a possible relationship between different SARS-CoV-2 immune responses [ 100 , 104 ], neurological disorders observed in long covid patients, and THOP1 involvement in MHC-class I regulation in COVID-19 patients [ 105 – 107 ].…”

Section: Discussionmentioning

confidence: 99%

“…A last point of strength of our computational approach is based on the ability of our pipeline to detect ACE2 structurally related proteins to be monitored as alternative cell-entry factors in those cells showing a low expression of ACE2. The highlighted structural relationships between ACE2, ACE, THOP1, and NLN might be useful for the scientific community that should monitor and evaluate the putative abilities of future SARS-CoV-2 variants and other related coronaviruses to use ACE2 structurally related proteins to penetrate host-cells, which might result even more dangerous due to the role of THOP1 in the regulation of MHC I cell-surface expression [ 105 – 107 ].…”

Section: Strengths and Limitationsmentioning

confidence: 99%

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Modeling SARS-CoV-2 spike/ACE2 protein–protein interactions for predicting the binding affinity of new spike variants for ACE2, and novel ACE2 structurally related human protein targets, for COVID-19 handling in the 3PM context

Tragni

Laera

et al. 2022

EPMA Journal

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Aims The rapid spread of new SARS-CoV-2 variants has highlighted the crucial role played in the infection by mutations occurring at the SARS-CoV-2 spike receptor binding domain (RBD) in the interactions with the human ACE2 receptor. In this context, it urgently needs to develop new rapid tools for quickly predicting the affinity of ACE2 for the SARS-CoV-2 spike RBD protein variants to be used with the ongoing SARS-CoV-2 genomic sequencing activities in the clinics, aiming to gain clues about the transmissibility and virulence of new variants, to prevent new outbreaks and to quickly estimate the severity of the disease in the context of the 3PM. Methods In our study, we used a computational pipeline for calculating the interaction energies at the SARS-CoV-2 spike RBD/ACE2 protein–protein interface for a selected group of characterized infectious variants of concern/interest (VoC/VoI). By using our pipeline, we built 3D comparative models of the SARS-CoV-2 spike RBD/ACE2 protein complexes for the VoC B.1.1.7-United Kingdom (carrying the mutations of concern/interest N501Y, S494P, E484K at the RBD), P.1-Japan/Brazil (RBD mutations: K417T, E484K, N501Y), B.1.351-South Africa (RBD mutations: K417N, E484K, N501Y), B.1.427/B.1.429-California (RBD mutations: L452R), the B.1.141 (RBD mutations: N439K), and the recent B.1.617.1-India (RBD mutations: L452R; E484Q) and the B.1.620 (RBD mutations: S477N; E484K). Then, we used the obtained 3D comparative models of the SARS-CoV-2 spike RBD/ACE2 protein complexes for predicting the interaction energies at the protein–protein interface. Results Along SARS-CoV-2 mutation database screening and mutation localization analysis, it was ascertained that the most dangerous mutations at VoC/VoI spike proteins are located mainly at three regions of the SARS-CoV-2 spike “boat-shaped” receptor binding motif, on the RBD domain. Notably, the P.1 Japan/Brazil variant present three mutations, K417T, E484K, N501Y, located along the entire receptor binding motif, which apparently determines the highest interaction energy at the SARS-CoV-2 spike RBD/ACE2 protein–protein interface, among those calculated. Conversely, it was also observed that the replacement of a single acidic/hydrophilic residue with a basic residue (E484K or N439K) at the “stern” or “bow” regions, of the boat-shaped receptor binding motif on the RBD, appears to determine an interaction energy with ACE2 receptor higher than that observed with single mutations occurring at the “hull” region or with other multiple mutants. In addition, our pipeline allowed searching for ACE2 structurally related proteins, i.e., THOP1 and NLN, which deserve to be investigated for their possible involvement in interactions with the SARS-CoV-2 spike protein, in those tissues showing a low expression of ACE2, or as a novel receptor for future spike variants. A freely available web-tool for the in silico calculation of the interaction energy at the SARS-CoV-2 spike RBD/ACE2 prot...

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Section: Discussionmentioning

confidence: 99%

Section: Strengths and Limitationsmentioning

confidence: 99%

Modeling SARS-CoV-2 spike/ACE2 protein–protein interactions for predicting the binding affinity of new spike variants for ACE2, and novel ACE2 structurally related human protein targets, for COVID-19 handling in the 3PM context

Tragni

Laera

et al. 2022

EPMA Journal

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“…This suggests the role of TOP on intracellular peptide metabolism and its consequent effects on receptors of serotonin and dopamine, which are known mediators of neuronal communication in many psychiatric disorders [64]. In addition, Visniauskas et al reported that sleep deprivation decreases TOP activity in the striatum and hypothalamus, which can potentially alter the processing of neuropeptides, and that processing of opioid peptides by TOP may be related to the increase in pain sensitivity in rats [22].…”

Section: Cytosolic Top Can Process Intracellular Peptides and Serve As A Natural Regulator Of Intracellular Signalingmentioning

confidence: 99%

“…In addition, compartmentalization and secretion of TOP can be modulated by a variety of factors, including calcium [20] and 14-3-3 epsilon [21]. Other non-conventional modulators of TOP activity have been reported, such as sleep deprivation [22] and mechanical shear [23,24], possibly mediated by G proteins.…”

Section: Introduction: Thimet Oligopeptidase-classical Function Regulation and Structurementioning

confidence: 99%

Thimet Oligopeptidase—A Classical Enzyme with New Function and New Form

Liu

Sigman

Bruce

et al. 2021

Immuno

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Peptidases generate bioactive peptides that can regulate cell signaling and mediate intercellular communication. While the processing of peptide precursors is initiated intracellularly, some modifications by peptidases may be conducted extracellularly. Thimet oligopeptidase (TOP) is a peptidase that processes neuroendocrine peptides with roles in mood, metabolism, and immune responses, among other functions. TOP also hydrolyzes angiotensin I to angiotensin 1–7, which may be involved in the pathophysiology of COVID-19 infection. Although TOP is primarily cytosolic, it can also be associated with the cell plasma membrane or secreted to the extracellular space. Recent work indicates that membrane-associated TOP can be released with extracellular vesicles (EVs) to the extracellular space. Here we briefly summarize the enzyme’s classical function in extracellular processing of neuroendocrine peptides, as well as its more recently understood role in intracellular processing of various peptides that impact human diseases. Finally, we discuss new findings of EV-associated TOP in the extracellular space.

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“…Furthermore, THOP1 appears to play a crucial role in the regulation of MHC I cell-surface expression [72][73][74]. Due to the shown high expression of THOP1 in several brain compartments and in the effector CD8 T-cells of COVID-19 patients [71], it raises the question about a possible relationship between different SARS-CoV-2 immune responses [75,76], neurological disorders observed in long covid patients, and THOP1 involvement in MHC-class I regulation in COVID-19 patients [77][78][79].…”

Section: Discussionmentioning

confidence: 99%

A modular molecular framework for quickly estimating the binding affinity of the spike protein of SARS-CoV-2 variants for ACE2, in presence of mutations at the spike receptor binding domain

Tragni

Laera

et al. 2021

Preprint

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The rapid spread of new SARS-CoV-2 variants needs the development of rapid tools for predicting the affinity of the mutated proteins responsible for the infection, i.e., the SARS-CoV-2 spike protein, for the human ACE2 receptor, aiming to understand if a variant can be more efficient in invading host cells. Here we show how our computational pipeline, previously used for studying SARS-CoV-2 spike receptor-binding domain (RBD)/ACE2 interactions and pre-/post-fusion conformational changes, can be used for predicting binding affinities of the human ACE2 receptor for the spike protein RBD of the characterized infectious variants of concern/interest B.1.1.7-UK (carrying the mutations N501Y, S494P, E484K at the RBD), P.1-Japan/Brazil (RBD mutations: K417N/T, E484K, N501Y), B.1.351-South Africa (RBD mutations: K417N, E484K, N501Y), B.1.427/B.1.429-California (RBD mutations: L452R), the B.1.141 variant (RBD mutations: N439K), and the recent B.1.617.1-India (RBD mutations: L452R; E484Q) and the B.1.620 (RBD mutations: S477N; E484K). Furthermore, we searched for ACE2 structurally related proteins that might be involved in interactions with the SARS-CoV-2 spike protein, in those tissues showing low ACE2 expression, revealing two new proteins, THOP1 and NLN, deserving to be investigated for their possible inclusion in the group of host-cell entry factors responsible for host-cell SARS-CoV-2 invasion and immunity response.

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Sleep deprivation changes thimet oligopeptidase (THOP1) expression and activity in rat brain

Cited by 3 publications

References 59 publications

Modeling SARS-CoV-2 spike/ACE2 protein–protein interactions for predicting the binding affinity of new spike variants for ACE2, and novel ACE2 structurally related human protein targets, for COVID-19 handling in the 3PM context

Modeling SARS-CoV-2 spike/ACE2 protein–protein interactions for predicting the binding affinity of new spike variants for ACE2, and novel ACE2 structurally related human protein targets, for COVID-19 handling in the 3PM context

Thimet Oligopeptidase—A Classical Enzyme with New Function and New Form

A modular molecular framework for quickly estimating the binding affinity of the spike protein of SARS-CoV-2 variants for ACE2, in presence of mutations at the spike receptor binding domain

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