Language
Country/Area
No result found
Escape strategies of influenza viruses: How does M2 help viruses enter cells?
Influenza A virus is a highly contagious virus that often causes seasonal flu. The M2 protein inside it is an important structure that enables the virus to effectively invade host cells by providing proton conduction. The working mechanism of M2 is not only crucial for the survival of the virus, but may also provide key clues for us to develop new antiviral drugs.
Structure and function of M2 protein
M2 protein is a proton-selective viroporin in the influenza A virus envelope. Its structure is composed of four identical M2 units, each of which contains 97 amino acid residues. These amino acids are divided into three parts:
- Extracellular N-terminal region (1st-23 amino acids)
- Transmembrane region (amino acids 24-46)
- Intracellular C-terminal region (amino acids 47-97)
"M2 channel protein, as an important component of the viral envelope, can form a highly selective, pH-regulated proton-conducting channel."
Through this channel, the virus is able to maintain the pH of its internal environment during entry into the host cell. When the virus enters the host cell through receptor-mediated endocytosis, acidification of the endosome activates the M2 channel, which allows protons to enter the viral core and create favorable conditions for viral replication.
Proton conduction and selectivity
The selectivity of M2 protein is highly dependent on its constituent histidine residue (His37), which exhibits superior proton conduction ability in a low pH environment. When His37 is replaced by other amino acids, the proton-selective activity disappears and the mutant M2 can transport sodium and potassium ions. This has drawn more attention to the key role of M2 protein in maintaining the intracellular environment of the host cell."The M2 channel can effectively activate the NLRP3 inflammasome pathway, thus playing an important role in antiviral immunity."
These results support the critical role of the structure and function of the M2 channel in the life cycle of different viruses and recommend therapeutic strategies targeting M2.
Inhibition and drug resistance
Currently, the anti-influenza drug amantadine is a known specific blocker of the M2 proton channel. The drug prevents the virus from unpacking by binding to and blocking the central pore of M2. However, influenza A viruses have developed widespread resistance to this drug, with resistance variants associated with the S31N mutation in particular being highly prevalent in circulating viruses.
"As of June 2021, the U.S. CDC no longer recommends the use of amantadine and its derivatives."
M2 protein of influenza B and C viruses
Influenza B and C viruses also encode proteins with similar functions, called BM2 and CM2, respectively. Although they have little similarity in sequence, their structure and mechanism are similar. The proton conduction ability of the BM2 protein is similar to that of M2 of influenza A, but it is completely insensitive to amantadine and its derivatives.
ConclusionAs we study the M2 protein, we are gaining a better understanding of how this channel helps the influenza virus enter cells. The unique properties of the M2 protein make it an important target for finding new antiviral therapies. In the face of the ever-changing influenza virus, can we find effective ways to fight this dangerous pathogen?
