Coronavirus membrane protein
From Wikipedia the free encyclopedia
The membrane (M) protein (previously called E1, sometimes also matrix protein) is an integral membrane protein that is the most abundant of the four major structural proteins found in coronaviruses.  The M protein organizes the assembly of coronavirus virions through protein-protein interactions with other M protein molecules as well as with the other three structural proteins, the envelope (E), spike (S), and nucleocapsid (N) proteins.
The M protein is a transmembrane protein with three transmembrane domains and is around 230 amino acid residues long. In SARS-CoV-2, the causative agent of Covid-19, the M protein is 222 residues long. Its membrane topology orients the C-terminus toward the cytosolic face of the membrane and thus into the interior of the virion. It has a short N-terminal segment and a larger C-terminal domain. Although the protein sequence is not well conserved across all coronavirus groups, there is a conserved amphipathic region near the C-terminal end of the third transmembrane segment.
M functions as a homodimer. Studies of the M protein in multiple coronaviruses by cryo-electron microscopy have identified two distinct functional protein conformations, thought to have different roles in forming protein-protein interactions with other structural proteins. M protein of SARS-CoV-2 is homologous to the prokaryotic sugar transport protein SemiSWEET. 
M is a glycoprotein whose glycosylation varies according to coronavirus subgroup; N-linked glycosylation is typically found in the alpha and gamma groups while O-linked glycosylation is typically found in the beta group. There are some exceptions; for example, in SARS-CoV, a betacoronavirus, the M protein has one N-glycosylation site. Glycosylation state does not appear to have a measurable effect on viral growth. No other post-translational modifications have been described for the M protein.
Expression and localization
|NCBI genome ID|
|Genome size||29,903 bases|
|Year of completion||2020|
The gene encoding the M protein is located toward the 3' end of the virus's positive-sense RNA genome, along with the genes for the other three structural proteins and various virus-specific accessory proteins. M is translated by membrane-bound polysomes to be inserted into the endoplasmic reticulum (ER) and trafficked to the endoplasmic reticulum-Golgi intermediate compartment (ERGIC), the intracellular compartment that gives rise to the coronavirus viral envelope, or to the Golgi apparatus. The exact localization is dependent on the specific virus protein. Investigations of the subcellular localization of the MERS-CoV M protein found C-terminal sequence signals associated with trafficking to the Golgi.
The primary function of the M protein is organizing assembly of new virions. It is involved in establishing viral shape and morphology. Individual M molecules interact with each other to form the viral envelope and may be able to exclude host cell proteins from the viral membrane. Studies of the SARS-CoV M protein suggest that M-M interactions involve both the N- and C-termini. Coronaviruses are moderately pleomorphic and conformational variations of M appear to be associated with virion size.
M forms protein-protein interactions with all three other major structural proteins. M is necessary but not sufficient for viral assembly; M and the E protein expressed together are reportedly sufficient to form virus-like particles, though some reports vary depending on experimental conditions and the specific virus studied. In some reports M appears to be capable of inducing membrane curvature, though others report M alone is insufficient for this and E is required. Although the E protein is not necessarily essential, it appears to be required for normal viral morphology and may be responsible for establishing curvature or initiating viral budding. M also appears to have functional roles in the later stages of viral maturation, secretion, and budding.
Incorporation of the spike protein (S) - which is required for assembly of infectious virions - is reported to occur though M interactions and may depend on specific conformations of M. The conserved amphipathic region C-terminal to the third transmembrane segment is important for spike interactions. Interactions with M appear to be required for correct subcellular localization of S at the viral budding site. M interacts directly with the nucleocapsid (N) protein without requiring the presence of RNA. This interaction appears to occur primarily through both proteins' C-termini.
Interactions with the immune system
The M protein is immunogenic and has been reported to be a determinant of humoral immunity. Cytotoxic T cell responses to M have been described. Antibodies to epitopes found in the M protein have been identified in patients recovered from severe acute respiratory syndrome (SARS).
Host cell entry
It has been reported that human coronavirus NL63 relies on the M protein as well as the S protein to mediate host cell interactions preceding viral entry. M is thought to bind heparan sulfate proteoglycans exposed on the cell surface.
Evolution and conservation
A study of SARS-CoV-2 sequences collected during the Covid-19 pandemic found that missense mutations in the M gene were relatively uncommon and suggested it was under purifying selection. Similar results have been described for broader population genetics analyses over a wider range of related viruses, finding that the sequences of M and several non-structural proteins in the coronavirus genome are most subject to evolutionary constraints.
- Solodovnikov, Alexey; Arkhipova, Valeria (2021-07-29). "Достоверно красиво: как мы сделали 3D-модель SARS-CoV-2" [Truly beautiful: how we made the SARS-CoV-2 3D model] (in Russian). N+1. Archived from the original on 2021-07-30. Retrieved 30 July 2021.
- Hu, Yongwu; Wen, Jie; Tang, Lin; Zhang, Haijun; Zhang, Xiaowei; Li, Yan; Wang, Jing; Han, Yujun; Li, Guoqing; Shi, Jianping; Tian, Xiangjun; Jiang, Feng; Zhao, Xiaoqian; Wang, Jun; Liu, Siqi; Zeng, Changqing; Wang, Jian; Yang, Huanming (May 2003). "The M Protein of SARS-CoV: Basic Structural and Immunological Properties". Genomics, Proteomics & Bioinformatics. 1 (2): 118–130. doi:10.1016/S1672-0229(03)01016-7. PMC 5172243. PMID 15626342.
- Thomas S. The Structure of the Membrane Protein of SARS-CoV-2 Resembles the Sugar Transporter SemiSWEET. Pathog Immun. 2020 Oct 19;5(1):342-363.
- Wong, Nicholas A.; Saier, Milton H. (28 January 2021). "The SARS-Coronavirus Infection Cycle: A Survey of Viral Membrane Proteins, Their Functional Interactions and Pathogenesis". International Journal of Molecular Sciences. 22 (3): 1308. doi:10.3390/ijms22031308. PMC 7865831. PMID 33525632.
- Neuman, Benjamin W.; Kiss, Gabriella; Kunding, Andreas H.; Bhella, David; Baksh, M. Fazil; Connelly, Stephen; Droese, Ben; Klaus, Joseph P.; Makino, Shinji; Sawicki, Stanley G.; Siddell, Stuart G.; Stamou, Dimitrios G.; Wilson, Ian A.; Kuhn, Peter; Buchmeier, Michael J. (April 2011). "A structural analysis of M protein in coronavirus assembly and morphology". Journal of Structural Biology. 174 (1): 11–22. doi:10.1016/j.jsb.2010.11.021. PMC 4486061. PMID 21130884.
- Tseng, Ying-Tzu; Wang, Shiu-Mei; Huang, Kuo-Jung; Lee, Amber I-Ru; Chiang, Chien-Cheng; Wang, Chin-Tien (April 2010). "Self-assembly of Severe Acute Respiratory Syndrome Coronavirus Membrane Protein". Journal of Biological Chemistry. 285 (17): 12862–12872. doi:10.1074/jbc.M109.030270. PMC 2857088. PMID 20154085.
- Schoeman, Dewald; Fielding, Burtram C. (December 2019). "Coronavirus envelope protein: current knowledge". Virology Journal. 16 (1): 69. doi:10.1186/s12985-019-1182-0. PMC 6537279. PMID 31133031.
- Masters, Paul S. (2006). "The Molecular Biology of Coronaviruses". Advances in Virus Research. 66: 193–292. doi:10.1016/S0065-3527(06)66005-3. ISBN 9780120398690. PMC 7112330. PMID 16877062.
- J Alsaadi, Entedar A; Jones, Ian M (April 2019). "Membrane binding proteins of coronaviruses". Future Virology. 14 (4): 275–286. doi:10.2217/fvl-2018-0144. PMC 7079996. PMID 32201500.
- Cao, Yipeng; Yang, Rui; Lee, Imshik; Zhang, Wenwen; Sun, Jiana; Wang, Wei; Meng, Xiangfei (June 2021). "Characterization of the SARS‐CoV ‐2 E Protein: Sequence, Structure, Viroporin, and Inhibitors". Protein Science. 30 (6): 1114–1130. doi:10.1002/pro.4075. PMC 8138525. PMID 33813796.
- Thomas S. The Structure of the Membrane Protein of SARS-CoV-2 Resembles the Sugar Transporter SemiSWEET. Pathog Immun. 2020 Oct 19;5(1):342-363
- Voß, Daniel; Pfefferle, Susanne; Drosten, Christian; Stevermann, Lea; Traggiai, Elisabetta; Lanzavecchia, Antonio; Becker, Stephan (2009). "Studies on membrane topology, N-glycosylation and functionality of SARS-CoV membrane protein". Virology Journal. 6 (1): 79. doi:10.1186/1743-422X-6-79. PMC 2705359. PMID 19534833.
- Ujike, Makoto; Taguchi, Fumihiro (3 April 2015). "Incorporation of Spike and Membrane Glycoproteins into Coronavirus Virions". Viruses. 7 (4): 1700–1725. doi:10.3390/v7041700. PMC 4411675. PMID 25855243.
- Perrier, Anabelle; Bonnin, Ariane; Desmarets, Lowiese; Danneels, Adeline; Goffard, Anne; Rouillé, Yves; Dubuisson, Jean; Belouzard, Sandrine (September 2019). "The C-terminal domain of the MERS coronavirus M protein contains a trans-Golgi network localization signal". Journal of Biological Chemistry. 294 (39): 14406–14421. doi:10.1074/jbc.RA119.008964. PMC 6768645. PMID 31399512.
- Goodsell, David S.; Voigt, Maria; Zardecki, Christine; Burley, Stephen K. (6 August 2020). "Integrative illustration for coronavirus outreach". PLOS Biology. 18 (8): e3000815. doi:10.1371/journal.pbio.3000815. PMC 7433897. PMID 32760062.
- Liu, Jun; Sun, Yeping; Qi, Jianxun; Chu, Fuliang; Wu, Hao; Gao, Feng; Li, Taisheng; Yan, Jinghua; Gao, George F. (15 October 2010). "The Membrane Protein of Severe Acute Respiratory Syndrome Coronavirus Acts as a Dominant Immunogen Revealed by a Clustering Region of Novel Functionally and Structurally Defined Cytotoxic T‐Lymphocyte Epitopes". The Journal of Infectious Diseases. 202 (8): 1171–1180. doi:10.1086/656315. PMC 7537489. PMID 20831383.
- Zheng, Yi; Zhuang, Meng-Wei; Han, Lulu; Zhang, Jing; Nan, Mei-Ling; Zhan, Peng; Kang, Dongwei; Liu, Xinyong; Gao, Chengjiang; Wang, Pei-Hui (December 2020). "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) membrane (M) protein inhibits type I and III interferon production by targeting RIG-I/MDA-5 signaling". Signal Transduction and Targeted Therapy. 5 (1): 299. doi:10.1038/s41392-020-00438-7. PMC 7768267. PMID 33372174.
- Pang, Hai; Liu, Yinggang; Han, Xueqing; Xu, Yanhui; Jiang, Fuguo; Wu, Donglai; Kong, Xiangang; Bartlam, Mark; Rao, Zihe (1 October 2004). "Protective humoral responses to severe acute respiratory syndrome-associated coronavirus: implications for the design of an effective protein-based vaccine". Journal of General Virology. 85 (10): 3109–3113. doi:10.1099/vir.0.80111-0. PMID 15448374.
- Naskalska, Antonina; Dabrowska, Agnieszka; Szczepanski, Artur; Milewska, Aleksandra; Jasik, Krzysztof Piotr; Pyrc, Krzysztof (October 2019). "Membrane Protein of Human Coronavirus NL63 Is Responsible for Interaction with the Adhesion Receptor". Journal of Virology. 93 (19): e00355-19. doi:10.1128/JVI.00355-19. PMC 6744225. PMID 31315999.
- Shen, Lishuang; Bard, Jennifer Dien; Triche, Timothy J.; Judkins, Alexander R.; Biegel, Jaclyn A.; Gai, Xiaowu (1 January 2021). "Emerging variants of concern in SARS-CoV-2 membrane protein: a highly conserved target with potential pathological and therapeutic implications". Emerging Microbes & Infections. 10 (1): 885–893. doi:10.1080/22221751.2021.1922097. PMC 8118436. PMID 33896413.
- Cagliani, Rachele; Forni, Diego; Clerici, Mario; Sironi, Manuela (June 2020). "Computational Inference of Selection Underlying the Evolution of the Novel Coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2". Journal of Virology. 94 (12): e00411-20. doi:10.1128/JVI.00411-20. PMC 7307108. PMID 32238584.