The influenza virus ion channel and maturation cofactor M2 is a cholesterol-binding protein
- PMID: 15221235
- DOI: 10.1007/s00249-004-0424-1
The influenza virus ion channel and maturation cofactor M2 is a cholesterol-binding protein
Abstract
The influenza-virus M2 protein has proton channel activity required for virus uncoating and maturation of hemagglutinin (HA) through low-pH compartments. The proton channel is cytotoxic in heterologous expression systems and can be blocked with rimantadine. In an independent, rimantadine-resistant function, M2, interacting with the M1 protein, controls the shape of virus particles. These bud from cholesterol-rich membrane rafts where viral glycoproteins and matrix (M1)/RNP complexes assemble. We demonstrate that M2 preparations from influenza virus-infected cells and from a baculovirus expression system contain 0.5-0.9 molecules of cholesterol per monomer. Sequence analyses of the membrane-proximal M2 endodomain reveal interfacial hydrophobicity, a cholesterol-binding motif first identified in peripheral benzodiazepine receptor and human immunodeficiency virus gp41, and an overlapping phosphatidylinositol 4,5-bisphosphate-binding motif. M2 induced rimantadine-reversible cytotoxicity in intrinsically cholesterol-free E. coli, and purified E. coli-expressed M2 functionally reconstituted into cholesterol-free liposomes supported rimantadine-sensitive proton translocation. Therefore, cholesterol was nonessential for M2 ion-channel function and cytotoxicity and for the effect of rimantadine. Only about 5-8% of both M2 preparations, regardless of cholesterol content, associated with detergent-resistant membranes. Cholesterol affinity and palmitoylation, in combination with a short transmembrane segment suggest M2 is a peripheral raft protein. Preference for the raft/non-raft interface may determine colocalization with HA during apical transport, the low level of M2 incorporated into the viral envelope and its undisclosed role in virus budding for which a model is presented. M2 may promote clustering and merger of rafts and the pinching-off (fission) of virus particles.
Similar articles
-
Lateral Organization of Influenza Virus Proteins in the Budozone Region of the Plasma Membrane.J Virol. 2017 Apr 13;91(9):e02104-16. doi: 10.1128/JVI.02104-16. Print 2017 May 1. J Virol. 2017. PMID: 28202765 Free PMC article.
-
Intrinsic membrane association of the cytoplasmic tail of influenza virus M2 protein and lateral membrane sorting regulated by cholesterol binding and palmitoylation.Biochem J. 2011 Aug 1;437(3):389-97. doi: 10.1042/BJ20110706. Biochem J. 2011. PMID: 21592088
-
Functional reconstitution in lipid vesicles of influenza virus M2 protein expressed by baculovirus: evidence for proton transfer activity.J Gen Virol. 1994 Dec;75 ( Pt 12):3477-84. doi: 10.1099/0022-1317-75-12-3477. J Gen Virol. 1994. PMID: 7527837
-
Influenza virus M2 protein and haemagglutinin conformation changes during intracellular transport.Acta Virol. 1995 Jun;39(3):171-81. Acta Virol. 1995. PMID: 8579000 Review.
-
Cholesterol-binding viral proteins in virus entry and morphogenesis.Subcell Biochem. 2010;51:77-108. doi: 10.1007/978-90-481-8622-8_3. Subcell Biochem. 2010. PMID: 20213541 Free PMC article. Review.
Cited by
-
Cholesterol and M2 Rendezvous in Budding and Scission of Influenza A Virus.Subcell Biochem. 2023;106:441-459. doi: 10.1007/978-3-031-40086-5_16. Subcell Biochem. 2023. PMID: 38159237
-
Molecular origins of asymmetric proton conduction in the influenza M2 channel.Biophys J. 2023 Jan 3;122(1):90-98. doi: 10.1016/j.bpj.2022.11.029. Epub 2022 Nov 19. Biophys J. 2023. PMID: 36403086 Free PMC article.
-
Enhancing neutralizing activity against influenza H1N1/PR8 by engineering a single-domain VL-M2 specific into a bivalent form.PLoS One. 2022 Aug 31;17(8):e0273934. doi: 10.1371/journal.pone.0273934. eCollection 2022. PLoS One. 2022. PMID: 36044435 Free PMC article.
-
ARHGAP1 Transported with Influenza Viral Genome Ensures Integrity of Viral Particle Surface through Efficient Budozone Formation.mBio. 2022 Jun 28;13(3):e0072122. doi: 10.1128/mbio.00721-22. Epub 2022 Apr 27. mBio. 2022. PMID: 35475647 Free PMC article.
-
Hydrophobic Residues at the Intracellular Domain of the M2 Protein Play an Important Role in Budding and Membrane Integrity of Influenza Virus.J Virol. 2022 May 11;96(9):e0037322. doi: 10.1128/jvi.00373-22. Epub 2022 Apr 11. J Virol. 2022. PMID: 35404081 Free PMC article.
References
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical