M2 proton channel
The Matrix-2 (M2) protein is a
Influenza B and C viruses encode proteins with similar function dubbed "BM2" and "CM2" respectively. They share little similarity with M2 at the sequence level, despite a similar overall structure and mechanism.[1]
Structure
Flu_M2 | |||||||||
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TCDB 1.A.19 | | ||||||||
OPM superfamily | 185 | ||||||||
OPM protein | 2kqt | ||||||||
|
In influenza A virus, M2 protein unit consists of three protein segments comprising 97 amino acid residues: (i) an extracellular
The amphipathic helix residues (46–62) within the cytoplasmic tail play role in
The two structures also suggest different binding sites for the adamantane class of anti-influenza drugs. According to the low pH crystal structure a single molecule of amantadine binds in the middle of the pore, surrounded by residues Val27, Ala30, Ser31 and Gly34. In contrast, the NMR structure showed four rimantadine molecules bind to the lipid facing outer surface of the pore, interacting with residues Asp44 and Arg45. However, a recent solid state NMR spectroscopy structure shows that the M2 channel has two binding sites for amantadine, one high affinity site is in the N terminal lumen, and a second low affinity site on the C terminal protein surface.[7]
Proton conductance and selectivity
The M2 ion channel of both influenza A is highly selective for protons. The channel is activated by low pH and has a low conductance.[8] Histidine residues at position 37 (His37) are responsible for this proton selectivity and pH modulation. When His37 is replaced with glycine, alanine, glutamic acid, serine or threonine, the proton selective activity is lost and the mutant can transport Na+ and K+ ions also. When imidazole buffer is added to cells expressing mutant proteins, the ion selectivity is partially rescued.[9]
Acharya et al. suggested that the conduction mechanism involves the exchange of protons between the His37 imidazole moieties of M2 and waters confined to the M2 bundle interior.[10] Water molecules within the pore form hydrogen-bonded networks or 'water wires' from the channel entrance to His37. Pore-lining carbonyl groups are well situated to stabilize hydronium ions via second-shell interactions involving bridging water molecules. A collective switch of hydrogen bond orientations may contribute to the directionality of proton flux as His37 is dynamically protonated and deprotonated in the conduction cycle.[11] The His37 residues form a box-like structure, bounded on either side by water clusters with well-ordered oxygen atoms near by. The conformation of the protein, which is intermediate between structures previously solved at higher and lower pH, suggests a mechanism by which conformational changes might facilitate asymmetric diffusion through the channel in the presence of a proton gradient. Moreover, protons diffusing through the channel need not be localized to a single His37 imidazole, but instead may be delocalized over the entire His-box and associated water clusters.
Function
The M2 channel protein is an essential component of the viral envelope because of its ability to form a highly selective, pH-regulated, proton-conducting channel. The M2 proton channel maintains pH across the viral envelope during
After its synthesis within the infected host cell, M2 is inserted into the endoplasmic reticulum (ER) and transported to the cell surface via trans-Golgi network (TGN). Within the acidic TGN, M2 transports H+ ions out of the lumen, and maintains hemagglutinin (HA) metastable configuration.[12] At its TGN localization, M2 protein's ion channel activity has been shown to effectively activate the NLRP3 inflammasome pathway.[13]
Other important functions of M2 are its role in formation of filamentous strains of influenza, membrane scission and the release of the budding virion. M2 stabilizes the virus budding site, and mutations of M2 that prevent its binding to M1 can impair filament formation at the site of budding.
Transport reaction
The generalized transport reaction catalyzed by the M2 channel is:
- H+ (out) ⇌ H+ (in)
Inhibition and resistance
The anti-influenza virus drug, amantadine, is a specific blocker of the M2 H+ channel. The drug binds in and occludes the central pore.[14] In the presence of amantadine, viral uncoating and disassembly is incomplete.[15] Mutations conferring resistance to adamantane drugs, including amantadine and rimantadine, occur in the transmembrane region and are widespread. The large majority of resistant viruses carry the S31N mutation.[16] Resistance to adamantanes among circulating influenza A viruses varies by region but has globally increased significantly since the early 2000s.[16][17] The US CDC has released information stating that most circulating strains are now resistant to the two drugs available, and as of June 2021, their use is not recommended.[18]
Influenza B and C M2 proteins
M2 proton channel | |||||||||||
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Identifiers | |||||||||||
Symbol | Flu_B_M2 | ||||||||||
Pfam | PF04772 | ||||||||||
InterPro | IPR006859 | ||||||||||
|
CM2 | |||||||||
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Identifiers | |||||||||
Symbol | CM2 | ||||||||
Pfam | PF03021 | ||||||||
InterPro | IPR004267 | ||||||||
|
Influenza B and C viruses encode virion proteins with similar proton-transducing function dubbed "BM2" and "CM2" respectively. They share little similarity with M2 at the sequence level, despite a similar overall structure and mechanism.[1][19]
BM2
The M2 protein of influenza B is 109 residue long, homo-tetramer and is a functional homolog of influenza A protein. There is almost no sequence homology between influenza AM2 and BM2 except for the HXXXW sequence motif in the TMS that is essential for channel function. Its proton conductance pH profile is similar to that of AM2. However, the BM2 channel activity is higher than that of AM2, and the BM2 activity is completely insensitive to amantadine and rimantadine.[1] The structure of the influenza B channel at resolutions of 1.4–1.5 Å, published in 2020, revealed that the channel opening mechanism is different from that of the influenza A channel.[20]
CM2
CM2 may play a role in genome packaging in virions.[21] CM2 adjusts intracellular pH, and is able to replace influenza A M2 in this capacity.[22]
See also
References
- ^ PMID 20451491.
- PMID 12183461.
- PMID 7508997.
- PMID 20850012.
- PMID 18235504.
- PMID 18235503.
- PMID 20130653.
- PMID 10722698.
- PMID 15784624.
- PMID 20689043.
- PMID 26578770.
- PMID 8666660.
- PMID 20383149.
- ^ PMID 26578770.
- PMID 8162442.
- ^ PMID 25768797.
- PMID 17570112.
- ^ "Influenza Antiviral Medications: Summary for Clinicians". Centers for Disease Control and Prevention. 6 May 2021. Retrieved 14 June 2021.
- PMID 10660588.
- S2CID 211017938.
- PMID 21106743.
- PMID 21917958.
External links
- M2+protein,+Influenza+A+virus at the U.S. National Library of Medicine Medical Subject Headings (MeSH)