The higher pH in the lumen may help in release of the virus. (16) This finding supports that the E protein pentamer of coronavirus could be a H + channel, transferring H + from lumen to cytosol. The increased pH protects spike protein and promotes the release of the virus from the cell. (20) As reported, the cell infected with coronavirus exhibited a remarkable increase in pH in the Golgi complex. Viroporins can transport different ions but usually prefer cations (H +, K +, Na +, and Ca 2+). (19) The narrow pore is suggested as a viroporin to regulate multiple stages of viral life circles. (13a,14,15) Similarly, the TMD of SARS-CoV-2 E protein was also found to form a five-helix buddle surrounding a narrow pore. (18) Synthetic peptides of the TMD of E protein can form dimers, trimers, and pentamers, (19) among which the pentametric structure is widely accepted and studied as a viroporin. The SARS-CoV E protein contains a short hydrophilic terminal, a large hydrophobic transmembrane domain (TMD), and a long hydrophilic carboxyl end ( Figure S2). (17) The study about the E protein is important to understand virulence mechanisms. (14,16) The recombined CoVs which lack E protein express crippled viral maturation and incompetent progeny. (15) The E protein is related to intracellular trafficking and participates in the viral assembly and budding. (14) The majority of the protein is located on the ER (endoplasmic reticulum), Golgi complex, and ERGIC (ER–Golgi intermediate compartment). Other than the S, N, and M proteins, the E protein is abundantly expressed in the infected cells but only a small percentage is assembled into the viral envelope. (13) The E protein is the smallest among four major structural proteins. (11) The N and the M protein serve as RNA genome-binding protein (12) and the most abundant structural protein of the viral envelope, respectively. (10) The S protein mainly regulates the binding with the ACE2 (angiotensin-converting enzyme) receptor of cells. (3a,9) The genome of coronavirus encodes four major structural proteins, which are the spike (S) protein, nucleocapsid (N) protein, membrane (M) protein, and envelope (E) protein. The SARS-CoV-2 is a positive-RNA strand virus that belongs to the family Coronaviridae. (8) Thus, it is urgent to understand the virulence mechanisms to prevent future outbreaks and to develop the remedies for COVID-19.
(4) In addition to severe pneumonia, the SARS-CoV-2 can also cause multi-organ damage, including cardiovascular disease, (5) reproductive risk, (6) mental illness, (7) and smell disfunction.
(3) So far, the disease has infected 106 million people and caused over 4 million deaths in the whole world. The disease caused by it is known as coronavirus disease 2019 (COVID-19). (1b,2) In December 2019, a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was discovered and now has already spread across the whole world. (1) After 10 years, the outbreak of a new coronavirus, named the Middle East respiratory syndrome coronavirus (MERS-CoV), spread in 27 countries, causing a 35% death rate. In 2002, the SARS-CoV-related severe acute respiratory syndrome (SARS) took 4 months to overwhelm 29 countries and killed 774 reported patients. The results indicate the importance of palmitoylation, which can help the drug design for the treatment of COVID-19.Ĭoronaviruses (CoVs) are notorious as the pathogens of numerous diseases in a wide range of vertebrates, including human beings. The electrostatic forces on the two sides of the palmitoylated E protein pentamer are more beneficial to attract cations in the lumen and to release cations into the cytosol. The structure of the palmitoylated E protein pentamer is more stable while the loss of palmitoylation caused the pore radius to reduce and even collapse. The results indicate that the cation transferring direction is more from the lumen to the cytosol. In this work, we applied molecular dynamic simulations and topological and electrostatic analyses to study the effects of palmitoylation on the E protein pentamer. The E protein pentamer is a viroporin, serving as an ion transferring channel in cells. The envelope (E) protein is an important structural protein, affecting virus assembly and budding. Therefore, understanding virulence mechanisms is important to prevent future outbreaks and for COVID-19 drug development. Its major effects resulted in over four million deaths around the whole world by August 2021. SARS-CoV-2 that caused COVID-19 has spread since the end of 2019.
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