Contents

Coronavirus membrane protein

Major structure in coronaviruses

Membrane protein
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
Symbol	CoV_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[edit]

The M protein is a transmembrane protein with three transmembrane domains and is around 230 amino acid residues long.^[8][9]InSARS-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[edit]

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[edit]

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 size	29,903 bases
Year of completion	2020
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[edit]

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

Viral assembly[edit]

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[edit]

The M protein in MERS-CoV, SARS-CoV, and SARS-CoV-2 has been described as an antagonistofinterferon 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] Antibodiestoepitopes 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[edit]

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[edit]

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[edit]