The M2 protein is a proton

Proton

The proton is a subatomic particle with the symbol or and a positive electric charge of 1 elementary charge. One or more protons are present in the nucleus of each atom, along with neutrons. The number of protons in each atom is its atomic number....

-selective ion channel

Ion channel

Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...

 protein

Protein

Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

, integral in the viral envelope

Viral envelope

Many viruses have viral envelopes covering their protein capsids. The envelopes typically are derived from portions of the host cell membranes , but include some viral glycoproteins. Functionally, viral envelopes are used to help viruses enter host cells...

 of the influenza

Influenza

Influenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals...

 A virus

Virus

A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...

. The channel itself is a homotetramer (consists of four identical M2 units), where the units are helices stabilized by two disulfide bond

Disulfide bond

In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...

s. It is activated by low pH

PH

In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...

.

Structure

The M2 protein unit consists of three protein domain

Protein domain

A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...

s: (i) the 24 amino acid

Amino acid

Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

s on the N-terminal end

N-terminal end

The N-terminus refers to the start of a protein or polypeptide terminated by an amino acid with a free amine group . The convention for writing peptide sequences is to put the N-terminus on the left and write the sequence from N- to C-terminus...

, exposed to the outside environment (the N-terminal methionine is removed from the peptide and the remaining 23 amino acid sequence is also known as the M2 ectodomain, or M2e); (ii) the 22 mostly hydrophobic amino acids in the transmembrane region; and (iii) the 52 amino acids on the C-terminal domain, exposed to the inside of the viral particle.
Two different high-resolution structures of truncated forms of M2 have been reported: the structure of a mutated form of the M2 transmembrane region (residues 22-46),
as well as a longer version of the protein (residues 18-60) containing the transmembrane region and a segment of the C-terminal domain.
The two structures also suggest different binding sites for the adamantane class of anti-influenza drugs. Moreover, the structure of the longer version (residues 18-60) baring the S31N drug-resistance mutation has also been determined
.

Function

The M2 protein has an important role in the life cycle of the influenza A virus. It is located in the viral envelope. It enables hydrogen ions to enter the viral particle (virion) from the endosome

Endosome

In biology, an endosome is a membrane-bound compartment inside eukaryotic cells. It is a compartment of the endocytic membrane transport pathway from the plasma membrane to the lysosome. Molecules internalized from the plasma membrane can follow this pathway all the way to lysosomes for...

, thus lowering the pH inside of the virus, which causes dissociation of the viral matrix protein M1 from the ribonucleoprotein

Ribonucleoprotein

Ribonucleoprotein is a nucleoprotein that contains RNA, i.e. it is an association that combines ribonucleic acid and protein together. A few known examples include the ribosome, the enzyme telomerase, vault ribonucleoproteins, and small nuclear RNPs , which are implicated in pre-mRNA splicing and...

 RNP. This is a crucial step in uncoating of the virus and exposing its content to the cytoplasm

Cytoplasm

The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...

 of the host cell.

Inhibition and resistance

The function of the M2 channel can be inhibited by antiviral drug

Antiviral drug

Antiviral drugs are a class of medication used specifically for treating viral infections. Like antibiotics for bacteria, specific antivirals are used for specific viruses...

s amantadine

Amantadine

Amantadine is the organic compound known formally as 1-adamantylamine or 1-aminoadamantane. The molecule consists of adamantane backbone that has an amino group substituted at one of the four methyne positions. This pharmaceutical is sold under the name Symmetrel for use both as an antiviral and an...

 and rimantadine

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. Both rimantadine and the similar drug...

, which then blocks the virus from taking over the host cell. The molecule of the drug binds to the transmembrane region, sterically blocking the channel. This stops the protons from entering the virion, which then does not disintegrate.

However, the M2 gene

Gene

A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

 is susceptible to mutation

Mutation

In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...

s. When one of five amino acids in the transmembrane region gets suitably substituted, the virus gains resistance to the existing M2 inhibitors. As the mutations are relatively frequent, presence of the selection factors (e.g. using amantadine for treatment of sick poultry) can lead to emergence of a resistant strain. The US CDC has released information stating that most strains are now resistant to the two drugs available, and their use should be discontinued.