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Membrane protein
Illustration of a SARS-CoV-2 virion
Model of the external structure of the SARS-CoV-2 virion. [1]
● Blue: envelope
● Turquoise: spike glycoprotein (S)
● Red: envelope proteins (E)
● Green: membrane proteins (M)
● Orange: glycans
Identifiers
SymbolCoV_M
Pfam PF01635
InterPro IPR002574
PROSITE PS51927
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

The membrane (M) protein (previously called E1, sometimes also matrix protein [2]) is an integral membrane protein that is the most abundant of the four major structural proteins found in coronaviruses. [3] [4] [5] 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. [4] [6] [7] [8]

Structure

The M protein is a transmembrane protein with three transmembrane domains and is around 230 amino acid residues long. [8] [9] In SARS-CoV-2, the causative agent of COVID-19, the M protein is 222 residues long. [10] 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. [8] [9]

M functions as a homodimer. [4] [5] 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. [5] M protein of SARS-CoV-2 is homologous to the prokaryotic sugar transport protein SemiSWEET. [11]

Post-translational modifications

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. [8] [9] There are some exceptions; for example, in SARS-CoV, a betacoronavirus, the M protein has one N-glycosylation site. [8] [6] Glycosylation state does not appear to have a measurable effect on viral growth. [6] [9] [12] No other post-translational modifications have been described for the M protein. [4]

Expression and localization

Genomic information
Genomic organisation of isolate Wuhan-Hu-1, the earliest sequenced sample of SARS-CoV-2, indicating the location of the M gene
NCBI genome ID 86693
Genome size29,903 bases
Year of completion2020
Genome browser ( UCSC)

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. [6] [8] M is translated by membrane-bound polysomes [6] 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. [8] [7] [6] The exact localization is dependent on the specific virus protein. [13] Investigations of the subcellular localization of the MERS-CoV M protein found C-terminal sequence signals associated with trafficking to the Golgi. [14]

Function

Illustration of a coronavirus virion in the respiratory mucosa, showing the positions of the four structural proteins and components of the extracellular environment. [15]

The M protein is the most abundant protein in coronavirus virions. [8] [5] [4] It is essential for viral replication. [4]

Viral assembly

The primary function of the M protein is organizing assembly of new virions. [4] It is involved in establishing viral shape and morphology. Individual M molecules interact with each other to form the viral envelope [7] [9] [8] and may be able to exclude host cell proteins from the viral membrane. [5] Studies of the SARS-CoV M protein suggest that M-M interactions involve both the N- and C-termini. [6] Coronaviruses are moderately pleomorphic and conformational variations of M appear to be associated with virion size. [5]

M forms protein-protein interactions with all three other major structural proteins. [4] [7] M is necessary but not sufficient for viral assembly; M and the E protein expressed together are reportedly sufficient to form virus-like particles, [7] though some reports vary depending on experimental conditions and the specific virus studied. [6] [13] In some reports M appears to be capable of inducing membrane curvature, [5] though others report M alone is insufficient for this and E is required. [7] 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. [7] M also appears to have functional roles in the later stages of viral maturation, secretion, and budding. [4]

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. [5] [13] The conserved amphipathic region C-terminal to the third transmembrane segment is important for spike interactions. [13] Interactions with M appear to be required for correct subcellular localization of S at the viral budding site. [12] M interacts directly with the nucleocapsid (N) protein without requiring the presence of RNA. [6] This interaction appears to occur primarily through both proteins' C-termini. [4]

Interactions with the immune system

The human HLA-A*0201 (red) and beta-2 microglobulin (green) in complex with a peptide derived from the M protein of SARS-CoV (yellow, shown as surface). From PDB: 3I6G​. [16]

The M protein in MERS-CoV, SARS-CoV, and SARS-CoV-2 has been described as an antagonist of interferon response. [4] [17]

The M protein is immunogenic and has been reported to be a determinant of humoral immunity. [4] Cytotoxic T cell responses to M have been described. [16] Antibodies to epitopes found in the M protein have been identified in patients recovered from severe acute respiratory syndrome (SARS). [18]

Other recent research has identified that SAS-COV-2 membrane protein when treated on human PBMC's causes a significant increase in pro inflammatory mediators such as TNF and IL-6. [19] The effects of exogenous SARS-COV-2 membrane protein challenge in mice was also studied. In these studies, exogenous membrane protein treated intra nasally caused a significant increase in pulmonary inflammation in mice leading to histological changes within the lungs. [20]

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. [21]

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. [22] 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. [23]

References

  1. ^ 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.
  2. ^ Hu Y, Wen J, Tang L, Zhang H, Zhang X, Li Y, et al. (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.
  3. ^ 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.
  4. ^ a b c d e f g h i j k l Wong NA, Saier MH (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.
  5. ^ a b c d e f g h Neuman BW, Kiss G, Kunding AH, Bhella D, Baksh MF, Connelly S, et al. (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.
  6. ^ a b c d e f g h i Tseng YT, Wang SM, Huang KJ, Lee AI, Chiang CC, Wang CT (April 2010). "Self-assembly of severe acute respiratory syndrome coronavirus membrane protein". The Journal of Biological Chemistry. 285 (17): 12862–12872. doi: 10.1074/jbc.M109.030270. PMC  2857088. PMID  20154085.
  7. ^ a b c d e f g Schoeman D, Fielding BC (May 2019). "Coronavirus envelope protein: current knowledge". Virology Journal. 16 (1): 69. doi: 10.1186/s12985-019-1182-0. PMC  6537279. PMID  31133031.
  8. ^ a b c d e f g h i Masters PS (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.
  9. ^ a b c d e J Alsaadi EA, Jones IM (April 2019). "Membrane binding proteins of coronaviruses". Future Virology. 14 (4): 275–286. doi: 10.2217/fvl-2018-0144. PMC  7079996. PMID  32201500.
  10. ^ Cao Y, Yang R, Lee I, Zhang W, Sun J, Wang W, Meng X (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.
  11. ^ 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
  12. ^ a b Voss D, Pfefferle S, Drosten C, Stevermann L, Traggiai E, Lanzavecchia A, Becker S (June 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.
  13. ^ a b c d Ujike M, Taguchi F (April 2015). "Incorporation of spike and membrane glycoproteins into coronavirus virions". Viruses. 7 (4): 1700–1725. doi: 10.3390/v7041700. PMC  4411675. PMID  25855243.
  14. ^ Perrier A, Bonnin A, Desmarets L, Danneels A, Goffard A, Rouillé Y, et al. (September 2019). "The C-terminal domain of the MERS coronavirus M protein contains a trans-Golgi network localization signal". The Journal of Biological Chemistry. 294 (39): 14406–14421. doi: 10.1074/jbc.RA119.008964. PMC  6768645. PMID  31399512.
  15. ^ Goodsell DS, Voigt M, Zardecki C, Burley SK (August 2020). "Integrative illustration for coronavirus outreach". PLOS Biology. 18 (8): e3000815. doi: 10.1371/journal.pbio.3000815. PMC  7433897. PMID  32760062.
  16. ^ a b Liu J, Sun Y, Qi J, Chu F, Wu H, Gao F, et al. (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.
  17. ^ Zheng Y, Zhuang MW, Han L, Zhang J, Nan ML, Zhan P, et al. (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.
  18. ^ Pang H, Liu Y, Han X, Xu Y, Jiang F, Wu D, et al. (October 2004). "Protective humoral responses to severe acute respiratory syndrome-associated coronavirus: implications for the design of an effective protein-based vaccine". The Journal of General Virology. 85 (Pt 10): 3109–3113. doi: 10.1099/vir.0.80111-0. PMID  15448374.
  19. ^ Haystead, T., Lee, E., Cho, K., Gullickson, G., Hughes, P., Krafsur, G., ... & Scarneo, S. (2023). Investigation of SARS-CoV-2 individual proteins reveals the in vitro and in vivo immunogenicity of membrane protein. Scientific Reports, 13(1), 22873.
  20. ^ Haystead, T., Lee, E., Cho, K., Gullickson, G., Hughes, P., Krafsur, G., ... & Scarneo, S. (2023). Investigation of SARS-CoV-2 individual proteins reveals the in vitro and in vivo immunogenicity of membrane protein. Scientific Reports, 13(1), 22873.
  21. ^ Naskalska A, Dabrowska A, Szczepanski A, Milewska A, Jasik KP, Pyrc K (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.
  22. ^ Shen L, Bard JD, Triche TJ, Judkins AR, Biegel JA, Gai X (December 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.
  23. ^ Cagliani R, Forni D, Clerici M, Sironi M (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.
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