M2 proton channel

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3D model of the flu virion. (M2 labeled in white.) Flu und legende color c.jpg
3D model of the flu virion. (M2 labeled in white.)

The Matrix-2 (M2) protein is a proton-selective viroporin, integral in the viral envelope of the influenza A virus. The channel itself is a homotetramer (consists of four identical M2 units), where the units are helices stabilized by two disulfide bonds, and is activated by low pH. The M2 protein is encoded on the seventh RNA segment together with the M1 protein. Proton conductance by the M2 protein in influenza A is essential for viral replication.

Contents

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
PDB 1nyj EBI.jpg
the closed state structure of m2 protein h+ channel by solid state nmr spectroscopy
Identifiers
SymbolFlu_M2
Pfam PF00599
InterPro IPR002089
SCOP2 1mp6 / SCOPe / SUPFAM
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 N-terminal domain (residues 1–23); (ii) a transmembrane segment (TMS) (residues 24–46); (iii) an intracellular C-terminal domain (residues 47–97). The TMS forms the pore of the ion channel. The important residues are the imidazole of His37 (pH sensor) and the indole of Trp41 (gate). [2] This domain is the target of the anti influenza drugs, amantadine and its ethyl derivative rimantadine, and probably also the methyl derivative of rimantadine, adapromine. The first 17 residues of the M2 cytoplasmic tail form a highly conserved amphipathic helix. [3]

The amphipathic helix residues (46–62) within the cytoplasmic tail play role in virus budding and assembly. The influenza virus utilizes these amphipathic helices in M2 to alter membrane curvature at the budding neck of the virus in a cholesterol dependent manner. [4] The residues 70–77 of cytoplasmic tail are important for binding to M1 and for the efficient production of infectious virus particles. This region also contains a caveolin binding domain (CBD). The C-terminal end of the channel extends into a loop (residues 47–50) that connects the trans membrane domain to the C-terminal amphipathic helix. (46–62). Two different high-resolution structures of truncated forms of M2 have been reported: the crystal structure of a mutated form of the M2 transmembrane region (residues 22–46), [5] as well as a longer version of the protein (residues 18–60) containing the transmembrane region and a segment of the C-terminal domain as studied by nuclear magnetic resonance (NMR). [6]

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 cell entry and across the trans-Golgi membrane of infected cells during viral maturation. As virus enters the host cell by receptor-mediated endocytosis, endosomal acidification occurs. This low pH activates the M2 channel, which brings protons into the virion core. Acidification of virus interior leads to weakening of electrostatic interaction and leads to dissociation between M1 and viral ribonucleoprotein (RNP) complexes. Subsequent membrane fusion releases the uncoated RNPs into the cytoplasm which is imported to the nucleus to start viral replication.

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 transmembrane helical tetramer of the influenza A virus M2 protein in complex with the channel-blocking drug amantadine (shown in red). Highly conserved tryptophan and histidine residues known to play key roles in mediating proton transport are shown as sticks. From PDB: 3C9J . M2 influenza A proton channel amantadine 3C9J.png
The transmembrane helical tetramer of the influenza A virus M2 protein in complex with the channel-blocking drug amantadine (shown in red). Highly conserved tryptophan and histidine residues known to play key roles in mediating proton transport are shown as sticks. From PDB: 3C9J ​.

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
Identifiers
SymbolFlu_B_M2
Pfam PF04772
InterPro IPR006859
CM2
Identifiers
SymbolCM2
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

Related Research Articles

Aquaporin Cellular membrane structure that selectively passes water

Aquaporins, also called water channels, are channel proteins from a larger family of major intrinsic proteins that form pores in the membrane of biological cells, mainly facilitating transport of water between cells. The cell membranes of a variety of different bacteria, fungi, animal and plant cells contain aquaporins through which water can flow more rapidly into and out of the cell than by diffusing through the phospholipid bilayer. Aquaporins have six membrane-spanning alpha helical domains with both carboxylic and amino terminals on the cytoplasmic side. Two hydrophobic loops contain conserved asparagine-proline-alanine which form a barrel surrounding a central pore-like region that contains additional protein density. Because aquaporins are usually always open and are prevalent in just about every cell type, this leads to a misconception that water readily passes through the cell membrane down its concentration gradient. Water can pass through the cell membrane through simple diffusion because it is a small molecule, and through osmosis, in cases where the concentration of water outside of the cell is greater than that of the inside. However, because water is a polar molecule this process of simple diffusion is relatively slow, and the majority of water passes through aquaporin.

Rimantadine

Rimantadine is an orally administered antiviral drug used to treat, and in rare cases prevent, influenzavirus A infection. When taken within one to two days of developing symptoms, rimantadine can shorten the duration and moderate the severity of influenza. Rimantadine can mitigate symptoms, including fever. Both rimantadine and the similar drug amantadine are derivates of adamantane. Rimantadine is found to be more effective than amantadine because when used the patient displays fewer symptoms. Rimantadine was approved by the Food and Drug Administration (FDA) in 1994.

Amantadine

Amantadine, sold under the brand name Gocovri among others, is a medication used to treat dyskinesia associated with parkinsonism and influenza caused by type A influenzavirus, though its use for the latter is no longer recommended due to widespread drug resistance. It acts as a nicotinic antagonist, dopamine agonist, and noncompetitive NMDA antagonist. The antiviral mechanism of action is antagonism of the influenzavirus A M2 proton channel, which prevents endosomal escape.

Voltage-gated ion channel type of ion channel transmembrane protein

Voltage-gated ion channels are a class of transmembrane proteins that form ion channels that are activated by changes in the electrical membrane potential near the channel. The membrane potential alters the conformation of the channel proteins, regulating their opening and closing. Cell membranes are generally impermeable to ions, thus they must diffuse through the membrane through transmembrane protein channels. They have a crucial role in excitable cells such as neuronal and muscle tissues, allowing a rapid and co-ordinated depolarization in response to triggering voltage change. Found along the axon and at the synapse, voltage-gated ion channels directionally propagate electrical signals. Voltage-gated ion-channels are usually ion-specific, and channels specific to sodium (Na+), potassium (K+), calcium (Ca2+), and chloride (Cl−) ions have been identified. The opening and closing of the channels are triggered by changing ion concentration, and hence charge gradient, between the sides of the cell membrane.

Chloride channel

Chloride channels are a superfamily of poorly understood ion channels specific for chloride. These channels may conduct many different ions, but are named for chloride because its concentration in vivo is much higher than other anions. Several families of voltage-gated channels and ligand-gated channels have been characterized in humans.

The Transporter Classification Database is an International Union of Biochemistry and Molecular Biology (IUBMB)-approved classification system for membrane transport proteins, including ion channels.

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Vpu protein

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Channel blocker

A channel blocker is the biological mechanism in which a particular molecule is used to prevent the opening of ion channels in order to produce a physiological response in a cell. Channel blocking is conducted by different types of molecules, such as cations, anions, amino acids, and other chemicals. These blockers act as ion channel antagonists, preventing the response that is normally provided by the opening of the channel.

NS2 (HCV)

Nonstructural protein 2 (NS2) is a viral protein found in the hepatitis C virus. It is also produced by influenza viruses, and is alternatively known as the nuclear export protein (NEP).

Viral neuraminidase

Viral neuraminidase is a type of neuraminidase found on the surface of influenza viruses that enables the virus to be released from the host cell. Neuraminidases are enzymes that cleave sialic acid groups from glycoproteins. Neuraminidase inhibitors are antiviral agents that inhibit influenza viral neuraminidase activity and are of major importance in the control of influenza.

Acid-sensing ion channel

Acid-sensing ion channels (ASICs) are neuronal voltage-insensitive sodium channels activated by extracellular protons permeable to Na+. ASIC1 also shows low Ca2+ permeability. ASIC proteins are a subfamily of the ENaC/Deg superfamily of ion channels. These genes have splice variants that encode for several isoforms that are marked by a suffix. In mammals, acid-sensing ion channels (ASIC) are encoded by five genes that produce ASIC protein subunits: ASIC1, ASIC2, ASIC3, ASIC4, and ASIC5. Three of these protein subunits assemble to form the ASIC, which can combine into both homotrimeric and heterotrimeric channels typically found in both the central nervous system and peripheral nervous system. However, the most common ASICs are ASIC1a and ASIC1a/2a and ASIC3. ASIC2b is non-functional on its own but modulates channel activity when participating in heteromultimers and ASIC4 has no known function. On a broad scale, ASICs are potential drug targets due to their involvement in pathological states such as retinal damage, seizures, and ischemic brain injury.

KcsA potassium channel

KcsA (Kchannel of streptomyces A) is a prokaryotic potassium channel from the soil bacterium Streptomyces lividans that has been studied extensively in ion channel research. The pH activated protein possesses two transmembrane segments and a highly selective pore region, responsible for the gating and shuttling of K+ ions out of the cell. The amino acid sequence found in the selectivity filter of KcsA is highly conserved among both prokaryotic and eukaryotic K+ voltage channels; as a result, research on KcsA has provided important structural and mechanistic insight on the molecular basis for K+ ion selection and conduction. As one of the most studied ion channels to this day, KcsA is a template for research on K+ channel function and its elucidated structure underlies computational modeling of channel dynamics for both prokaryotic and eukaryotic species.

Adapromine

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Viroporin

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Robert A. Lamb

Robert A. Lamb is a British American virologist. He is the Kenneth F. Burgess Professor at Northwestern University and since 1991, and an investigator of the Howard Hughes Medical Institute. From 1990 to 2016, he was the John Evans Professor of Molecular and Cellular Biology at Northwestern University.

James J. Chou American chemist

James J. Chou (周界文) is a Chinese American scientist and Professor of Biological Chemistry and Molecular Pharmacology at the Harvard Medical School. He is known for pioneering the use of Nuclear Magnetic Resonance (NMR) Spectroscopy to reveal the structural details of the membrane regions of cell surface proteins, particularly those of immune receptors and viral membrane proteins.

Mei Hong (chemist) Chinese-American chemist

Mei Hong is a Chinese-American biophysical chemist and Professor of Chemistry at the Massachusetts Institute of Technology. She is known for her creative development and application of solid-state nuclear magnetic resonance (ssNMR) spectroscopy to elucidate the structures and mechanisms of membrane proteins, plant cell walls, and amyloid proteins. She has received a number of recognitions for her work, including the American Chemical Society Nakanishi Prize in 2021, Günther Laukien Prize in 2014, the Protein Society Young Investigator award in 2012, and the American Chemical Society’s Pure Chemistry award in 2003.

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References

  1. 1 2 3 Pielak RM, Chou JJ (February 2011). "Influenza M2 proton channels". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1808 (2): 522–9. doi:10.1016/j.bbamem.2010.04.015. PMC   3108042 . PMID   20451491.
  2. ↑ Tang Y, Zaitseva F, Lamb RA, Pinto LH (October 2002). "The gate of the influenza virus M2 proton channel is formed by a single tryptophan residue". The Journal of Biological Chemistry. 277 (42): 39880–6. doi: 10.1074/jbc.M206582200 . PMID   12183461.
  3. ↑ Holsinger LJ, Nichani D, Pinto LH, Lamb RA (March 1994). "Influenza A virus M2 ion channel protein: a structure-function analysis". Journal of Virology. 68 (3): 1551–63. doi:10.1128/JVI.68.3.1551-1563.1994. PMC   236612 . PMID   7508997.
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  5. ↑ Stouffer AL, Acharya R, Salom D, Levine AS, Di Costanzo L, Soto CS, Tereshko V, Nanda V, Stayrook S, DeGrado WF (January 2008). "Structural basis for the function and inhibition of an influenza virus proton channel". Nature. 451 (7178): 596–9. Bibcode:2008Natur.451..596S. doi:10.1038/nature06528. PMC   3889492 . PMID   18235504.
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  7. ↑ Cady SD, Schmidt-Rohr K, Wang J, Soto CS, Degrado WF, Hong M (February 2010). "Structure of the amantadine binding site of influenza M2 proton channels in lipid bilayers". Nature. 463 (7281): 689–92. Bibcode:2010Natur.463..689C. doi:10.1038/nature08722. PMC   2818718 . PMID   20130653.
  8. ↑ Mould JA, Li HC, Dudlak CS, Lear JD, Pekosz A, Lamb RA, Pinto LH (March 2000). "Mechanism for proton conduction of the M(2) ion channel of influenza A virus". The Journal of Biological Chemistry. 275 (12): 8592–9. doi: 10.1074/jbc.275.12.8592 . PMID   10722698.
  9. ↑ Venkataraman P, Lamb RA, Pinto LH (June 2005). "Chemical rescue of histidine selectivity filter mutants of the M2 ion channel of influenza A virus". The Journal of Biological Chemistry. 280 (22): 21463–72. doi: 10.1074/jbc.M412406200 . PMID   15784624.
  10. ↑ Acharya R, Carnevale V, Fiorin G, Levine BG, Polishchuk AL, Balannik V, Samish I, Lamb RA, Pinto LH, DeGrado WF, Klein ML (August 2010). "Structure and mechanism of proton transport through the transmembrane tetrameric M2 protein bundle of the influenza A virus". Proceedings of the National Academy of Sciences of the United States of America. 107 (34): 15075–80. Bibcode:2010PNAS..10715075A. doi: 10.1073/pnas.1007071107 . PMC   2930543 . PMID   20689043.
  11. ↑ Thomaston JL, Alfonso-Prieto M, Woldeyes RA, Fraser JS, Klein ML, Fiorin G, DeGrado WF (November 2015). "High-resolution structures of the M2 channel from influenza A virus reveal dynamic pathways for proton stabilization and transduction". Proceedings of the National Academy of Sciences of the United States of America. 112 (46): 14260–5. Bibcode:2015PNAS..11214260T. doi: 10.1073/pnas.1518493112 . PMC   4655559 . PMID   26578770.
  12. ↑ Sakaguchi T, Leser GP, Lamb RA (May 1996). "The ion channel activity of the influenza virus M2 protein affects transport through the Golgi apparatus". The Journal of Cell Biology. 133 (4): 733–47. doi:10.1083/jcb.133.4.733. PMC   2120830 . PMID   8666660.
  13. ↑ Ichinohe T, Pang IK, Iwasaki A (May 2010). "Influenza virus activates inflammasomes via its intracellular M2 ion channel". Nature Immunology. 11 (5): 404–10. doi:10.1038/ni.1861. PMC   2857582 . PMID   20383149.
  14. 1 2 Thomaston JL, Alfonso-Prieto M, Woldeyes RA, Fraser JS, Klein ML, Fiorin G, DeGrado WF (November 2015). "High-resolution structures of the M2 channel from influenza A virus reveal dynamic pathways for proton stabilization and transduction". Proceedings of the National Academy of Sciences of the United States of America. 112 (46): 14260–5. Bibcode:2015PNAS..11214260T. doi: 10.1073/pnas.1518493112 . PMC   4655559 . PMID   26578770.
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  16. 1 2 Dong G, Peng C, Luo J, Wang C, Han L, Wu B, et al. (2015-03-13). "Adamantane-resistant influenza a viruses in the world (1902-2013): frequency and distribution of M2 gene mutations". PLOS ONE. 10 (3): e0119115. Bibcode:2015PLoSO..1019115D. doi: 10.1371/journal.pone.0119115 . PMC   4358984 . PMID   25768797.
  17. ↑ Deyde VM, Xu X, Bright RA, Shaw M, Smith CB, Zhang Y, et al. (July 2007). "Surveillance of resistance to adamantanes among influenza A(H3N2) and A(H1N1) viruses isolated worldwide". The Journal of Infectious Diseases. 196 (2): 249–57. doi: 10.1086/518936 . PMID   17570112.
  18. ↑ "Influenza Antiviral Medications: Summary for Clinicians". Centers for Disease Control and Prevention. 6 May 2021. Retrieved 14 June 2021.
  19. ↑ Kukol A, Arkin IT (February 2000). "Structure of the influenza C virus CM2 protein transmembrane domain obtained by site-specific infrared dichroism and global molecular dynamics searching". The Journal of Biological Chemistry. 275 (6): 4225–9. doi: 10.1074/jbc.275.6.4225 . PMID   10660588.
  20. ↑ Mandala VS, Loftis AR, Shcherbakov AA, Pentelute BL, Hong M (February 2020). "Atomic structures of closed and open influenza B M2 proton channel reveal the conduction mechanism". Nature Structural & Molecular Biology . 27 (2): 160–167. doi:10.1038/s41594-019-0371-2. PMC   7641042 . PMID   32015551. S2CID   211017938.
  21. ↑ Furukawa T, Muraki Y, Noda T, Takashita E, Sho R, Sugawara K, Matsuzaki Y, Shimotai Y, Hongo S (February 2011). "Role of the CM2 protein in the influenza C virus replication cycle". Journal of Virology. 85 (3): 1322–9. doi: 10.1128/JVI.01367-10 . PMC   3020500 . PMID   21106743.
  22. ↑ Stewart SM, Pekosz A (January 2012). "The influenza C virus CM2 protein can alter intracellular pH, and its transmembrane domain can substitute for that of the influenza A virus M2 protein and support infectious virus production". Journal of Virology. 86 (2): 1277–81. doi:10.1128/JVI.05681-11. PMC   3255851 . PMID   21917958.
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