M2protein

M2 protein, short for matrix protein 2, is a small, integral membrane protein of influenza A virus. It is encoded by the M segment of the viral genome and is produced by splicing of the M RNA to generate a 97-amino-acid protein. M2 is one of the few virion-associated ion channels and is present in virions as well as in infected cells.

The protein has a modular structure consisting of an N-terminal extracellular ectodomain (about residues 1–24), a single transmembrane helix (residues ~25–43) that forms the proton-conducting channel, and a cytoplasmic tail (residues ~44–97) that interacts with matrix protein M1 and ribonucleoprotein complexes during assembly and uncoating. In functional form, M2 forms homotetramers in the membrane, creating a pH-gated proton channel that is activated in the acidic endosomal environment.

Functionally, M2 mediates proton flow from the endosome into the viral interior after endocytosis, promoting dissociation of ribonucleoproteins from M1 and enabling genome uncoating and release into the cytoplasm. The channel activity also influences virion interior conditions and intracellular trafficking. M2 is the target of the antiviral drugs amantadine and rimantadine, which block proton conductance. Widespread resistance due to mutations in the transmembrane region, notably Ser31Asn, has limited clinical use of these drugs.

A portion of M2, the extracellular ectodomain (M2e), is relatively conserved and has been explored as a candidate for universal influenza vaccines, though its low natural immunogenicity requires adjuvants or specialized delivery. The M segment encoding M1 and M2 shows variability among subtypes, shaping viral evolution and host interactions.