Investigating ion transport inside the pentameric ion channel encoded in COVID-19 E protein

Saurabh, Kumar; Solovchuk, Maxim; Sheu, Tony W. H.

doi:10.1103/physreve.102.052408

“…Tomar and Arkin [18] revealed that the SARS-CoV-2 E protein may be an ion channel viroporin. Further, Saurabh and colleagues [19] We can infer that the tertiary structure of the E protein is the same in SARS-CoV-2 as in ZC45 and ZXC21, since the amino acid sequences are identical. Further, we can infer that all strains of SARS-CoV-2 that have developed since the outbreak have almost the same tertiary structure, since 98.8% of SARS-CoV-2 strains are highly conserved, with an extremely low mutation rate: 1.2% of SARS-CoV-2 strains had gene mutations (synonymous and nonsynonymous) from the Wuhan reference strain [22].…”

Section: Introductionmentioning

confidence: 93%

“…Although the origin of SARS-CoV-2 is still under investigation, two bat SARS-like (SL) coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21, should be taken into account. One of the earliest studies on COVID- 19 RaTG13 is the closest relative to SARS-CoV-2, with a genome that is generally acknowledged to be 96% identical to it, and was claimed to have been discovered…”

Section: Introductionmentioning

confidence: 99%

Universal COVID-19 Vaccine Targeting SARS-CoV-2 Envelope Protein

Tsai¹

2021

WJV

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The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), had caused over 382 million cases and over 2.7 million deaths globally as of 23 March 2021. By that date, at least 10 SARS-CoV-2 variants had emerged. The transmissibility and lethality of the variants are higher than those of the Wuhan reference strain. Therefore, a universal vaccine for the reference strain and all variants (present and future) is indispensable. The coronavirus envelope (E) protein is an integral membrane protein crucial to the viral lifecycle and the pathogenesis of coronaviruses. The SARS-CoV-2 E protein has a postsynaptic density protein 95/Drosophila disc large tumor suppressor/zonula occludens-1 (PDZ) binding motif (PBM), and its interaction with PDZ-domain-2 of the human tight junction protein may interrupt the integrity of lung epithelium. Furthermore, the SARS-CoV-2 E protein itself is a homopentameric cation channel viroporin, which may be involved in viral release. This protein is thus a potential target for the development of a universal COVID-19 vaccine, because of its highly conserved amino acid sequence. The variant mutations occur mainly in the spike protein, and conservation of E protein remained in most Variants of Concern (VOC). Only one of the extant VOC have mutations in the E protein that P71L mutation occurs in the South African variant 501Y.V2 (B.1.351). If a vaccine is designed to target E protein, two scenarios are possible: 1) SARS-CoV-2 maintains a highly conserved E protein amino acid sequence, rendering the virus consistently or permanently susceptible to the vaccine; or 2) the E protein mutates and new variants evolve accordingly. In scenario 2, the tertiary structure and function of the E protein homopentameric cation channel viroporin, PBM, or other aspects affecting pathogenicity would be attenuated. Either scenario would thus ameliorate the pandemic. I therefore propose that a vaccine targeting the SARS-CoV-2 E protein would be effective against the Wuhan reference strain and all current and fu-

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“…152,153 The modulation by viroporins on the opening/closure of multiple pores in the cell membrane tends to regulate cation transmembrane movement, but also endoplasmic reticulum cation release. 5,251 In fact, these small hydrophobic proteins are encoded by the virus and are oligomerized in the membrane of host cells, leading to the formation of hydrophilic pores. This activity disrupts several cellular functions, including membrane permeability, calcium homeostasis, membrane remodeling and glycoprotein trafficking.…”

Section: C) Viroporinsmentioning

confidence: 99%

COVID-19, Cation Dysmetabolism, Sialic Acid, CD147, ACE2, Viroporins, Hepcidin and Ferroptosis: A Possible Unifying Hypothesis

Cavezzi

¹

,

Menicagli

²

,

Troiani³

et al. 2022

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Background: iron and calcium dysmetabolism, with hyperferritinemia, hypoferremia, hypocalcemia and anemia have been documented in the majority of COVID-19 patients at later/worse stages. Furthermore, complementary to ACE2, both sialic acid (SA) molecules and CD147 proved relevant host receptors for SARS-CoV-2 entry, which explains the viral attack to multiple types of cells, including erythrocytes, endothelium and neural tissue. Several authors advocated that cell ferroptosis may be the core and final cell degenerative mechanism. Methods: a literature research was performed in several scientific search engines, such as PubMed Central, Cochrane Library, Chemical Abstract Service. More than 500 articles were retrieved until mid-December 2021, to highlight the available evidence about the investigated issues. Results: based on COVID-19 literature data, we have highlighted a few pathophysiological mechanisms, associated with virus-based cation dysmetabolism, multi-organ attack, mitochondria degeneration and ferroptosis. Our suggested elucidated pathological sequence is: a) spike protein subunit S1 docking with sialylated membrane glycoproteins/receptors (ACE2, CD147), and S2 subunit fusion with the lipid layer; b) cell membrane morpho-functional changes due to the consequent electro-chemical variations and viroporin action, which induce an altered ion channel function and intracellular cation accumulation; c) additional intracellular iron concentration due to a deregulated hepcidin-ferroportin axis, with higher hepcidin levels. Viral invasion may also affect erythrocytes/erythroid precursors, endothelial cells and macrophages, through SA and CD147 receptors, with relative hemoglobin and iron/calcium dysmetabolism. AB0 blood group, hemochromatosis, or environmental elements may represent possible factors which affect individual susceptibility to COVID-19. Conclusions: our literature analysis confirms the combined role of SA molecules, ACE2, CD147, viroporins and hepcidin in determining the cation dysmetabolism and final ferroptosis in the cells infected by SARS-CoV-2. The altered ion channels and electrochemical gradients of the cell membrane have a pivotal role in the virus entry and cell dysmetabolism, with subsequent multi-organ immune-inflammatory degeneration and erythrocyte/hemoglobin alterations.

show abstract

“…150,151 The modulation by viroporins on the opening/closure of multiple pores in the cell membrane tends to regulate cation transmembrane movement, but also endoplasmic reticulum cation release. 5,249 In fact, these small hydrophobic proteins are encoded by the virus and are oligomerized in the membrane of host cells, leading to the formation of hydrophilic pores. This activity disrupts several cellular functions, including membrane permeability, calcium homeostasis, membrane remodeling and glycoprotein trafficking.…”

Section: C) Viroporinsmentioning

confidence: 99%

“…Several authors have highlighted that iron dysmetabolism (and probable blood components denaturation), together with cell membrane morpho-functional deregulation, represent specific early biochemical phenomena in this infection. [1][2][3][4][5][6] Hyperferritinemia, low serum iron and low total iron binding capacity (TIBC) have been definitely linked to COVID-19 severity, and these elements have been considered relevant prognostic factors. 1,[7][8][9][10][11][12][13][14] Similarly, a series of possible treatments aimed at controlling iron dysmetabolism have been proposed.…”

Section: Introductionmentioning

confidence: 99%

COVID-19, Cation Dysmetabolism, Sialic Acid, CD147, ACE2, Viroporins, Hepcidin and Ferroptosis: A Possible Unifying Hypothesis

Cavezzi

¹

,

Menicagli

²

,

Troiani

³

et al. 2022

View full text Add to dashboard Cite

Background: iron and calcium dysmetabolism, with hyperferritinemia, hypoferremia, hypocalcemia and anemia have been documented in the majority of COVID-19 patients at later/worse stages. Furthermore, complementary to ACE2, both sialic acid (SA) molecules and CD147 proved relevant host receptors for SARS-CoV-2 entry, which explains the viral attack to multiple types of cells, including erythrocytes, endothelium and neural tissue. Several authors advocated that cell ferroptosis may be the core and final cell degenerative mechanism. Methods: a literature research was performed in several scientific search engines, such as PubMed Central, Cochrane Library, Chemical Abstract Service. More than 500 articles were retrieved until mid-December 2021, to highlight the available evidence about the investigated issues. Results: based on COVID-19 literature data, we have highlighted a few pathophysiological mechanisms, associated with virus-based cation dysmetabolism, multi-organ attack, mitochondria degeneration and ferroptosis. Our suggested elucidated pathological sequence is: a) spike protein subunit S1 docking with sialylated membrane glycoproteins/receptors (ACE2, CD147), and S2 subunit fusion with the lipid layer; b) cell membrane morpho-functional changes due to the consequent electro-chemical variations and viroporin action, which induce an altered ion channel function and intracellular cation accumulation; c) additional intracellular iron concentration due to a deregulated hepcidin-ferroportin axis, with higher hepcidin levels. Viral invasion may also affect erythrocytes/erythroid precursors, endothelial cells and macrophages, through SA and CD147 receptors, with relative hemoglobin and iron/calcium dysmetabolism. AB0 blood group, hemochromatosis, or environmental elements may represent possible factors which affect individual susceptibility to COVID-19. Conclusions: our literature analysis confirms the combined role of SA molecules, ACE2, CD147, viroporins and hepcidin in determining the cation dysmetabolism and final ferroptosis in the cells infected by SARS-CoV-2. The altered ion channels and electrochemical gradients of the cell membrane have a pivotal role in the virus entry and cell dysmetabolism, with subsequent multi-organ immune-inflammatory degeneration and erythrocyte/hemoglobin alterations.

show abstract

Investigating ion transport inside the pentameric ion channel encoded in COVID-19 E protein

Cited by 12 publications

References 43 publications

Universal COVID-19 Vaccine Targeting SARS-CoV-2 Envelope Protein

Universal COVID-19 Vaccine Targeting SARS-CoV-2 Envelope Protein

COVID-19, Cation Dysmetabolism, Sialic Acid, CD147, ACE2, Viroporins, Hepcidin and Ferroptosis: A Possible Unifying Hypothesis

COVID-19, Cation Dysmetabolism, Sialic Acid, CD147, ACE2, Viroporins, Hepcidin and Ferroptosis: A Possible Unifying Hypothesis

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