1.A.39 The Type C Influenza Virus CM2 Channel (CM2-C) Family The mechanisms and functions of viral channel proteins have been reviewed by Fischer and Hsu (2011) and Fischer et al. (2012). The CM2 putative channel of type C influenza virus is 139 aas long and shows two putative TMSs. The first is a cleavage signal sequence. The mature, processed glycoprotein (115 aas) is a type I membrane protein with an extracellular N-terminus, glycosylated on Asn-26, a single central TMS, and a cytoplasmic C-terminus (N_out-C_in). It is a disulfide-linked homotetramer (Fischer and Sansom, 2002). The effects of N-linked glycosylation, disulfide-linked oligomerization, palmitoylation of CM2 and phosphorylation on virus replication have been analyzed. Phosphorylation of CM2 plays a role in efficient virus replication, probably through the addition of a negative charge to the Ser78 phosphorylation site. (Goto et al. 2017). CM2 and a chimeric influenza A virus M2 protein (MCM), containing the CM2 transmembrane domain, could alter cytosolic pH when expressed from cDNAs, but only M2 and MCM, not CM2 could restore infectious virus production to M2-deficient influenza A viruses (Stewart and Pekosz 2012). Thus, while the CM2 ion channel activity is similar to that of M2, sequences in the extracellular and/or cytoplasmic domains play important roles in infectious virus production. As noted above, CM2 has probable roles in the genome packaging and uncoating processes of the virus replication cycle (Furukawa et al. 2011). The influenza virus D viroporin, DM2, matrix protein P42 or M1, is very similar to the CM2 channel protein and similarly forms a channel (Kesinger et al. 2018).
References:
Fischer, W.B. and H.J. Hsu. (2011). Viral channel forming proteins - modeling the target. Biochim. Biophys. Acta. 1808: 561-571.
Fischer, W.B. and M.S. Sansom. (2002). Viral ion channels: structure and function. Biochim. Biophys. Acta 1561: 27-45.
Fischer, W.B., Y.T. Wang, C. Schindler, and C.P. Chen. (2012). Mechanism of function of viral channel proteins and implications for drug development. Int Rev Cell Mol Biol 294: 259-321.
Furukawa, T., Y. Muraki, T. Noda, E. Takashita, R. Sho, K. Sugawara, Y. Matsuzaki, Y. Shimotai, and S. Hongo. (2011). Role of the CM2 protein in the influenza C virus replication cycle. J. Virol. 85: 1322-1329.
Goto, T., Y. Shimotai, Y. Matsuzaki, Y. Muraki, R. Sho, K. Sugawara, and S. Hongo. (2017). Effect of Phosphorylation of CM2 Protein on Influenza C Virus Replication. J. Virol. 91:.
Kesinger, E., J. Liu, A. Jensen, C.P. Chia, A. Demers, and H. Moriyama. (2018). Influenza D virus M2 protein exhibits ion channel activity in Xenopus laevis oocytes. PLoS One 13: e0199227.
Stewart, S.M. and A. Pekosz. (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. J. Virol. 86: 1277-1281.
Examples:
TC#	Name	Organismal Type	Example
1.A.39.1.1	The Type C influenza M2-like protein, CM2, of 374 aas and 2 TMSs near the C-terninus of the protein (Stewart and Pekosz 2012).	Influenza virus	CM2 of Type C influenza virus

1.A.39.1.2	P42 protein of 387 aas and 2 TMSs.		*P42 of Influenza D virus* (D/swine/Oklahoma)**

1.A.39.1.3	CM2 protein of 105 aas and 2 TMSs. A processed version of 1.A.39.1.1.		CM2 of Influenza virus type C