Coronavirus nucleocapsid protein

Last updated
Nucleocapsid protein
Coronavirus. SARS-CoV-2.png
Model of the external structure of the SARS-CoV-2 virion. [1] The N protein, contained entirely within the virion, is not visible.
● Blue: envelope
● Turquoise: spike glycoprotein (S)
● Red: envelope proteins (E)
● Green: membrane proteins (M)
● Orange: glycans
Identifiers
SymbolCoV_nucleocap
Pfam PF00937
InterPro IPR001218
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

The nucleocapsid (N) protein is a protein that packages the positive-sense RNA genome of coronaviruses to form ribonucleoprotein structures enclosed within the viral capsid. [2] [3] The N protein is the most highly expressed of the four major coronavirus structural proteins. [2] In addition to its interactions with RNA, N forms protein-protein interactions with the coronavirus membrane protein (M) during the process of viral assembly. [2] [3] N also has additional functions in manipulating the cell cycle of the host cell. [3] [4] The N protein is highly immunogenic and antibodies to N are found in patients recovered from SARS and COVID-19. [5]

Contents

History

COVID-19 was first identified in January 2020. A patient in the state of Washington was given a diagnosis of coronavirus infection on 20 January. A group of scientists based at the Centers for Disease Control and Prevention in Atlanta, Georgia isolated the virus from nasopharyngeal and oropharyngeal swabs and were able to characterize the genomic sequence, replication properties and cell culture tropism from the swabs. They made available the virus to the wider scientific community shortly thereafter "by depositing it into two virus reagent repositories". [6]

Structure

X-ray crystallography structure of the dimer formed by two C-terminal domains from the SARS-CoV-2 N protein. 6wzo chainAB.png
X-ray crystallography structure of the dimer formed by two C-terminal domains from the SARS-CoV-2 N protein.

The N protein is composed of two main protein domains connected by an intrinsically disordered region (IDR) known as the linker region, with additional disordered segments at each terminus. [2] [3] A third small domain at the C-terminal tail appears to have an ordered alpha helical secondary structure and may be involved in the formation of higher-order oligomeric assemblies. [7] In SARS-CoV, the causative agent of SARS, the N protein is 422 amino acid residues long [2] and in SARS-CoV-2, the causative agent of COVID-19, it is 419 residues long. [7] [8]

Both the N-terminal and C-terminal domains are capable of binding RNA. The C-terminal domain forms a dimer that is likely to be the native functional state. [2] Parts of the IDR, particularly a conserved sequence motif rich in serine and arginine residues (the SR-rich region), may also be implicated in dimer formation, though reports on this vary. [2] [3] Although higher-order oligomers formed through the C-terminal domain have been observed crystallographically, it is unclear if these structures have a physiological role. [2] [9]

The C-terminal dimer has been structurally characterized by X-ray crystallography for several coronaviruses and has a highly conserved structure. [7] The N-terminal domain - sometimes known as the RNA-binding domain, though other parts of the protein also interact with RNA - has also been crystallized and has been studied by nuclear magnetic resonance spectroscopy in the presence of RNA. [10]

Post-translational modifications

The N protein is post-translationally modified by phosphorylation at sites located in the IDR, particularly in the SR-rich region. [2] [11] SARS-CoV-2 nucleocapsid (N) protein is arginine methylated by protein arginine methyltransferase 1 (PRMT1) at residues R95 and R177. Type I PRMT inhibitor (MS023) or substitution of R95 or R177 with lysine inhibited interaction of N protein with the 5’-UTR of SARS-CoV-2 genomic RNA, a property required for viral packaging | doi: 10.1016/j.jbc.2021.100821 | PMID 34029587. In several coronaviruses, ADP-ribosylation of the N protein has also been reported. [12] [11] With unclear functional significance, the SARS-CoV N protein has been observed to be SUMOylated and the N proteins of several coronaviruses including SARS-CoV-2 have been observed to be proteolytically cleaved. [11] [13] [14]

Expression and localization

The N protein is the most highly expressed in host cells of the four major structural proteins. [2] Like the other structural proteins, the gene encoding the N protein is located toward the 3' end of the genome. [3]

N protein is localized primarily to the cytoplasm. [3] In many coronaviruses, a population of N protein is localized to the nucleolus, [3] [4] [15] thought to be associated with its effects on the cell cycle. [4]

Function

Genome packaging and viral assembly

Illustration of a coronavirus virion in the respiratory mucosa, showing the positions of the four structural proteins and components of the extracellular environment. Pbio.3000815.g001.PNG L.png
Illustration of a coronavirus virion in the respiratory mucosa, showing the positions of the four structural proteins and components of the extracellular environment.
NMR structure of the SARS-CoV-2 N protein N-terminal domain (red) in complex with double-stranded RNA (orange and yellow). 7acs all states.png
NMR structure of the SARS-CoV-2 N protein N-terminal domain (red) in complex with double-stranded RNA (orange and yellow).

The N protein binds to RNA to form ribonucleoprotein (RNP) structures for packaging the genome into the viral capsid. [2] [3] The RNP particles formed are roughly spherical and are organized in flexible helical structures inside the virus. [2] [3] Formation of RNPs is thought to involve allosteric interactions between RNA and multiple RNA-binding regions of the protein. [2] [9] Dimerization of N is important for assembly of RNPs. Encapsidation of the genome occurs through interactions between N and M. [2] [3] N is essential for viral assembly. [3] N also serves as a chaperone protein for the formation of RNA structure in the genomic RNA. [3] [9]

Genomic and subgenomic RNA synthesis

Synthesis of genomic RNA appears to involve participation by the N protein. N is physically colocalized with the viral RNA-dependent RNA polymerase early in the replication cycle and forms interactions with non-structural protein 3, a component of the replicase-transcriptase complex. [3] Although N appears to facilitate efficient replication of genomic RNA, it is not required for RNA transcription in all coronaviruses. [3] [17] In at least one coronavirus, transmissible gastroenteritis virus (TGEV), N is involved in template switching in the production of subgenomic mRNAs, a process that is a distinctive feature of viruses in the order Nidovirales . [3] [17] [18]

Cell cycle effects

Coronaviruses manipulate the cell cycle of the host cell through various mechanisms. In several coronaviruses, including SARS-CoV, the N protein has been reported to cause cell cycle arrest in S phase through interactions with cyclin-CDK. [3] [4] In SARS-CoV, a cyclin box-binding region in the N protein can serve as a cyclin-CDK phosphorylation substrate. [3] Trafficking of N to the nucleolus may also play a role in cell cycle effects. [4] More broadly, N may be involved in reduction of host cell protein translation activity. [3]

Immune system effects

The N protein is involved in viral pathogenesis via its effects on components of the immune system. In SARS-CoV, [3] [19] [20] MERS-CoV, [21] and SARS-CoV-2, [22] N has been reported as suppressing interferon responses.

Evolution and conservation

The sequences and structures of N proteins from different coronaviruses, particularly the C-terminal domains, appear to be well conserved. [2] [7] [23] Similarities between the structure and topology of the N proteins of coronaviruses and arteriviruses suggest a common evolutionary origin and supports the classification of these two groups in the common order Nidovirales . [2] [3]

Examination of SARS-CoV-2 sequences collected during the COVID-19 pandemic found that missense mutations were most common in the central linker region of the protein, suggesting this relatively unstructured region is more tolerant of mutations than the structured domains. [7] A separate study of SARS-CoV-2 sequences identified at least one site in the N protein under positive selection. [24]

The N protein's properties of being well conserved, not appearing to recombine frequently, and producing a strong T-cell response have led to it being studied as a potential target for coronavirus vaccines. [25] [26] [23] [27] The vaccine candidate UB-612 is one such experimental vaccine that targets the N protein, along with other viral proteins, to attempt to induce broad immunity. [28] [29]

Related Research Articles

<span class="mw-page-title-main">Coronavirus</span> Subfamily of viruses in the family Coronaviridae

Coronaviruses are a group of related RNA viruses that cause diseases in mammals and birds. In humans and birds, they cause respiratory tract infections that can range from mild to lethal. Mild illnesses in humans include some cases of the common cold, while more lethal varieties can cause SARS, MERS and COVID-19, which is causing the ongoing pandemic. In cows and pigs they cause diarrhea, while in mice they cause hepatitis and encephalomyelitis.

<span class="mw-page-title-main">SARS-related coronavirus</span> Species of coronavirus causing SARS and COVID-19

Severe-acute-respiratory-syndrome–related coronavirus is a species of virus consisting of many known strains. Two strains of the virus have caused outbreaks of severe respiratory diseases in humans: severe acute respiratory syndrome coronavirus 1, which caused the 2002–2004 outbreak of severe acute respiratory syndrome (SARS), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is causing the ongoing pandemic of COVID-19. There are hundreds of other strains of SARSr-CoV, which are only known to infect non-human mammal species: bats are a major reservoir of many strains of SARSr-CoV; several strains have been identified in Himalayan palm civets, which were likely ancestors of SARS-CoV-1.

<span class="mw-page-title-main">Defective interfering particle</span>

Defective interfering particles (DIPs), also known as defective interfering viruses, are spontaneously generated virus mutants in which a critical portion of the particle's genome has been lost due to defective replication or non-homologous recombination. The mechanism of their formation is presumed to be as a result of template-switching during replication of the viral genome, although non-replicative mechanisms involving direct ligation of genomic RNA fragments have also been proposed. DIPs are derived from and associated with their parent virus, and particles are classed as DIPs if they are rendered non-infectious due to at least one essential gene of the virus being lost or severely damaged as a result of the defection. A DIP can usually still penetrate host cells, but requires another fully functional virus particle to co-infect a cell with it, in order to provide the lost factors.

<span class="mw-page-title-main">Rabies virus</span> Species of virus

Rabies virus, scientific name Rabies lyssavirus, is a neurotropic virus that causes rabies in animals, including humans. Rabies transmission can occur through the saliva of animals and less commonly through contact with human saliva. Rabies lyssavirus, like many rhabdoviruses, has an extremely wide host range. In the wild it has been found infecting many mammalian species, while in the laboratory it has been found that birds can be infected, as well as cell cultures from mammals, birds, reptiles and insects. Rabies is reported in more than 150 countries and on all continents except Antarctica. The main burden of disease is reported in Asia and Africa, but some cases have been reported also in Europe in the past 10 years, especially in returning travellers.

<i>Coronaviridae</i> Family of viruses in the order Nidovirales

Coronaviridae is a family of enveloped, positive-strand RNA viruses which infect amphibians, birds, and mammals. The group includes the subfamilies Letovirinae and Orthocoronavirinae; the members of the latter are known as coronaviruses.

The NS1 influenza protein (NS1) is a viral nonstructural protein encoded by the NS gene segments of type A, B and C influenza viruses. Also encoded by this segment is the nuclear export protein (NEP), formally referred to as NS2 protein, which mediates the export of influenza virus ribonucleoprotein (RNP) complexes from the nucleus, where they are assembled.

<i>Murine coronavirus</i> Species of virus

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<span class="mw-page-title-main">Coronavirus packaging signal</span> Regulartory element in coronaviruses

The Coronavirus packaging signal is a conserved cis-regulatory element found in Betacoronavirus. It has an important role in regulating the packaging of the viral genome into the capsid. As part of the viral life cycle, within the infected cell, the viral genome becomes associated with viral proteins and assembles into new infective progeny viruses. This process is called packaging and is vital for viral replication.

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<span class="mw-page-title-main">ORF7a</span> Gene found in coronaviruses of the Betacoronavirus genus

ORF7a is a gene found in coronaviruses of the Betacoronavirus genus. It expresses the Betacoronavirus NS7A protein, a type I transmembrane protein with an immunoglobulin-like protein domain. It was first discovered in SARS-CoV, the virus that causes severe acute respiratory syndrome (SARS). The homolog in SARS-CoV-2, the virus that causes COVID-19, has about 85% sequence identity to the SARS-CoV protein.

<i>Human coronavirus HKU1</i> Species of virus

Human coronavirus HKU1 (HCoV-HKU1) is a species of coronavirus in humans and animals. It causes an upper respiratory disease with symptoms of the common cold, but can advance to pneumonia and bronchiolitis. It was first discovered in January 2004 from one man in Hong Kong. Subsequent research revealed it has global distribution and earlier genesis.

<span class="mw-page-title-main">Coronavirus envelope protein</span> Major structure in coronaviruses

The envelope (E) protein is the smallest and least well-characterized of the four major structural proteins found in coronavirus virions. It is an integral membrane protein less than 110 amino acid residues long; in SARS-CoV-2, the causative agent of Covid-19, the E protein is 75 residues long. Although it is not necessarily essential for viral replication, absence of the E protein may produce abnormally assembled viral capsids or reduced replication. E is a multifunctional protein and, in addition to its role as a structural protein in the viral capsid, it is thought to be involved in viral assembly, likely functions as a viroporin, and is involved in viral pathogenesis.

<span class="mw-page-title-main">Coronavirus membrane protein</span> Major structure in coronaviruses

The membrane (M) 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.

<span class="mw-page-title-main">Coronavirus spike protein</span> Glycoprotein spike on a viral capsid or viral envelope

Spike (S) glycoprotein is the largest of the four major structural proteins found in coronaviruses. The spike protein assembles into trimers that form large structures, called spikes or peplomers, that project from the surface of the virion. The distinctive appearance of these spikes when visualized using negative stain transmission electron microscopy, "recalling the solar corona", gives the virus family its main name.

<span class="mw-page-title-main">ORF3a</span> Gene found in coronaviruses of the subgenus Sarbecovirus

ORF3a is a gene found in coronaviruses of the subgenus Sarbecovirus, including SARS-CoV and SARS-CoV-2. It encodes an accessory protein about 275 amino acid residues long, which is thought to function as a viroporin. It is the largest accessory protein and was the first of the SARS-CoV accessory proteins to be described.

ORF7b is a gene found in coronaviruses of the genus Betacoronavirus, which expresses the accessory protein Betacoronavirus NS7b protein. It is a short, highly hydrophobic transmembrane protein of unknown function.

<span class="mw-page-title-main">ORF8</span> Gene that encodes a viral accessory protein

ORF8 is a gene that encodes a viral accessory protein, Betacoronavirus NS8 protein, in coronaviruses of the subgenus Sarbecovirus. It is one of the least well conserved and most variable parts of the genome. In some viruses, a deletion splits the region into two smaller open reading frames, called ORF8a and ORF8b - a feature present in many SARS-CoV viral isolates from later in the SARS epidemic, as well as in some bat coronaviruses. For this reason the full-length gene and its protein are sometimes called ORF8ab. The full-length gene, exemplified in SARS-CoV-2, encodes a protein with an immunoglobulin domain of unknown function, possibly involving interactions with the host immune system. It is similar in structure to the ORF7a protein, suggesting it may have originated through gene duplication.

ORF6 is a gene that encodes a viral accessory protein in coronaviruses of the subgenus Sarbecovirus, including SARS-CoV and SARS-CoV-2. It is not present in MERS-CoV. It is thought to reduce the immune system response to viral infection through interferon antagonism.

<span class="mw-page-title-main">ORF9b</span> Gene

ORF9b is a gene that encodes a viral accessory protein in coronaviruses of the subgenus Sarbecovirus, including SARS-CoV and SARS-CoV-2. It is an overlapping gene whose open reading frame is entirely contained within the N gene, which encodes coronavirus nucleocapsid protein. The encoded protein is 97 amino acid residues long in SARS-CoV and 98 in SARS-CoV-2, in both cases forming a protein dimer.

References

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