Structural characteristics of the M2 protein of influenza a viruses: Evidence that it forms a tetrameric channe

Abstract The evidence presented shows that the M2 protein of influenza A viruses exists in infected cells as a homotetramer composed of two disulfide-linked dimers held together by noncovalent interactions. The amphiphilic nature of the transmembrane α-helical domain is consistent with the protein forming a transmembrane channel with which amantadine, the specific anti-influenza A drug, interacts. Together these features provide a structural basis for the hypothesis that M2 has a proton translocation function capable of regulating the pH of vesicles of the trans-Golgi network, a role important in promoting the correct maturation of the hemagglutinin glycoprotein.

[1]  E. Albuquerque,et al.  Structure-activity relationships of amantadine. I. Interaction of the N-alkyl analogues with the ionic channels of the nicotinic acetylcholine receptor and electrically excitable membrane. , 1982, Molecular pharmacology.

[2]  H. Eggers,et al.  Inhibition of uncoating of fowl plague virus by l-adamantanamine hydrochloride. , 1969, Virology.

[3]  R. Lamb,et al.  Determination of the orientation of an integral membrane protein and sites of glycosylation by oligonucleotide-directed mutagenesis: influenza B virus NB glycoprotein lacks a cleavable signal sequence and has an extracellular NH2-terminal region , 1986, Molecular and cellular biology.

[4]  H. Lester,et al.  An open-channel blocker interacts with adjacent turns of α-helices in the nicotinic acetylcholine receptor , 1990, Neuron.

[5]  P. Y. Chou,et al.  Empirical predictions of protein conformation. , 1978, Annual review of biochemistry.

[6]  W. J. Bean,et al.  Biologic potential of amantadine-resistant influenza A virus in an avian model. , 1989, The Journal of infectious diseases.

[7]  P. Collins,et al.  The 1A protein of respiratory syncytial virus is an integral membrane protein present as multiple, structurally distinct species , 1989, Journal of virology.

[8]  T. Klimkait,et al.  The human immunodeficiency virus type 1-specific protein vpu is required for efficient virus maturation and release , 1990, Journal of virology.

[9]  J. Skehel,et al.  The molecular basis of the specific anti‐influenza action of amantadine. , 1985, The EMBO journal.

[10]  J. Thornton.  Disulphide bridges in globular proteins. , 1981, Journal of molecular biology.

[11]  J. Skehel,et al.  Molecular basis of resistance of influenza A viruses to amantadine. , 1986, The Journal of antimicrobial chemotherapy.

[12]  A. Hay.  The Mechanism of Action of Amantadine and Rimantadine Against Influenza Viruses , 1989 .

[13]  J. Sodroski,et al.  Functional role of human immunodeficiency virus type 1 vpu. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[14]  A. Bukrinskaya,et al.  Uncoating of a rimantadine-resistant variant of influenza virus in the presence of rimantadine. , 1982, The Journal of general virology.

[15]  R. Lamb,et al.  Identification and predicted sequence of a previously unrecognized small hydrophobic protein, SH, of the paramyxovirus simian virus 5 , 1985, Journal of virology.

[16]  R. Ruigrok,et al.  The specific inhibition of influenza A virus maturation by amantadine: an electron microscopic examination. , 1991, The Journal of general virology.

[17]  R. Lamb,et al.  Influenza A virus M2 protein: monoclonal antibody restriction of virus growth and detection of M2 in virions , 1988, Journal of virology.

[18]  R. Belshe,et al.  Palmitoylation of the influenza A virus M2 protein. , 1990, Virology.

[19]  A. Douglas,et al.  Specific structural alteration of the influenza haemagglutinin by amantadine. , 1990, The EMBO journal.

[20]  A. Eldefrawi,et al.  [3H]Phencyclidine interactions with the nicotinic acetylcholine receptor channel and its inhibition by psychotropic, antipsychotic, opiate, antidepressant, antibiotic, antiviral, and antiarrhythmic drugs. , 1982, Molecular pharmacology.

[21]  A. R. Smith,et al.  Identification of a new membrane-associated polypeptide specified by the coronavirus infectious bronchitis virus. , 1990, The Journal of general virology.

[22]  R. Lamb,et al.  Influenza virus M2 protein is an integral membrane protein expressed on the infected-cell surface , 1985, Cell.

[23]  H. Lester,et al.  Evidence that the M2 membrane-spanning region lines the ion channel pore of the nicotinic receptor. , 1988, Science.

[24]  C B Hall,et al.  Genetic basis of resistance to rimantadine emerging during treatment of influenza virus infection , 1988, Journal of virology.

[25]  R. Doms,et al.  Quaternary structure of influenza virus hemagglutinin after acid treatment , 1986, Journal of virology.