SARS-COV-2 Structural Proteins

Structural proteins are essential in many steps of the infection, they are implied in viral genome production, replication, virion-receptor attachment, viron and viroporin formation that will promote virus entry into the host, proliferation and spread of the infection. (2)

Spike glycoprotein

The envelope of corona-virion contains protruding projection from its surface called spike proteins (or S proteins).

The Spike glycoprotein mediates the virus attachment to host cell surface receptors ACE2 and facilitates virus entry by assisting fusion between viral and host cell membranes. It is the most exposed and immunogenic viral protein and hence a target of choice for diagnostic and therapeutic assays.

The Spike glycoprotein of SARS-CoV-2 is a trimeric macromolecule with two furin-like protease cleavage sites. One of the sites is at the boundary between S1 and S2 subunits having poly-basic residues, which is characteristic of SARS-CoV-2. The other cleavage site is located within the S2 subunit.

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SARS-CoV-2 Spike Structure

A. Spike proteins form trimers, each consisting of a short intracellular C fragment, a transmembrane moiety and an ectodomain element. The ectodomain is constituted of two subunits S1 and S2. On the S1 subunit, there is a receptor-binding domain (RBD) that recognizes and binds ACE2.
B. SP: signal peptide; NTD: N-terminal domain; RBD: receptor binding domain; RBM: receptor binding motif; FP: fusion peptide; HR1: heptad repeat 1; HR2: heptad repeat 2; TM: transmembrane domain; CD: cytoplasmic domain. The S1/S2 cleavage site is indicated.

Nucleocapsid (N)

N protein is express in the early stage of infection and is the most abundant protein It forms a core of a ribonucleoprotein by binding to viral RNA. It helps RNA to enter in the cell and to interact with cellular components. (3)

N protein has diverse roles including:

  • Promoting inflammation trough COX2
  • Decrease immune response by inhibiting type 1 interferon(4)
  • Interfering with cell cycle by inhibiting CDK complex and by decreasing B23 phosphorylation (5,6)

SARS-CoV-2 nucleocapsid protein structure

A. N protein forms an “X” shape due to the CTD domain. It is rich in helix and hydrophobe residues that favor binding to nucleic acid and lead to the neutralization of the charges (2)
B. NTD: N-terminal domain; SRL: (SR)-Rich Linker; CTD: C-Terminal domain.

Envelope protein (E)

SARS-CoV-2 Envelop protein (E-protein) is conserved across β-coronaviruses. It is a tiny integral membrane protein that pentamerize to form ionic pore across the membrane called viroporins. It is essential for viral assembly and release.(2)

Membrane protein (M)

Membrane glycoprotein (M) is conserved across the β-coronaviruses. It has a triple transmembrane domain and promotes spike installation (7). It is known to inhibit NFκB by interacting with IKKβ (7)

SARS-CoV-2 Life Cycle

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SARS-COV-2 Non-Structural Proteins and peptides

Introduction

In addition to the four structural proteins, the SARS-CoV2 genome encodes 16 non-structural proteins (NSPs) essential for virus replication but also to elicit the immune response and represent targets to develop future prophylactic and therapeutic approaches against COVID-19 (9). Replication and transcription of the coronavirus are done by a protein complex called RTC (replication/transcription complex)

Some data about protein function in SARS-Cov-2 are not yet known but their homology to their homolog in other Coronaviruses suggests their function might be the same.

Nsp1
It might be implied in the suppression of type I IFN expression like Nsp1 of SARS-CoV (10)

Nsp2
Its exact role is not yet known, it interacts with PHB1 and 2 host proteins, implied in mitochondria biogenesis (11)

Nsp3 : PL protease
The Papain-Like Protease participates to the cleavage of pp1a polyprotein into 11 non-structural proteins (Nsp1 to 11) (12)

PLpro activity assay kit

Nsp3/Nsp4/Nsp6 complex
The Nsp3, Nsp4 and Nsp6 proteins interact to form a complex to induce double-membrane vesicles(13)

3C-like protease is the principal protease of SARS-CoV2 and is essential for RNA replication. It cleaves the polyprotein Orfa with Nsp3 (14). It also cleaves the C-terminus from Nsp4 to Nsp16.

3CLPro activity assay kit

This complex gives rise to the RNA polymerase complex performing de novo initiation and primers extensions to trigger RNA synthesis. (15,16)

Nsp9
This protein binds to RNA to improve replication. (17)

Nsp10/Nsp16 complex
These proteins are N7 and 2’O-methyltransferases that cap viral mRNA for efficient translation and to escape immune response. (18)

Nsp11
Is a short peptide (13 aa) overlapping Nsp10 but its function is still unknown.

Nsp13
NSP13 is the virus helicase, allowing the duplex RNA to unwind and being accessible.(15)

Nsp14
Nsp14 is an exoribonuclease comprised in the RTC complex. It is implied in proofreading and recombination.

Nsp15 (NendoU)
NendoU (Nidoviral RNA uridylate‐specific endoribonuclease) is an endonuclease comprised in the RTC complex.

SARS-COV-2 Accessory Proteins and Peptides

The end of the SARS-CoV genome encodes for 9 additional proteins called Accessory proteins.

Orf3a

This protein is responsible for channel formation. It is essential for infectivity, virulence, and virus release (19)

Orf3b

It’s a small peptide of 22 aa overlapping with Orfa and is a potential IFN-1 antagonist (20)

Orf6

In SARS-CoV, Orf6 is an IFN antagonist. It has been shown to disrupt transportation of transcriptions factors (e.g. STAT1) (21,22)

Orf7a

In SARS-CoV ORF7a blocks glycosylation of BST-2 by its binding to this growth factor known to interact with IFN. (23)

Orf7b

This peptide of 43 aa overlap the sequence of ORF7a. (24)

Orf7b/Orf8

A deletion in ORF7b and ORF8 leads to a fusion protein has been found in various region and lead to deletion of 382 nucleotides that removes transcription regulatory sequence increasing N gene transcription.  This deletion leads to virus attenuation and reduced replication but leads to immune evasion (25)

Orf8

Orf8 is a less conserved protein compared to SARS-CoV (only 30% homology). It is implied in recognition by the immune system and transcription of N protein. (25)

Orf9b

It interacts with mitochondrial import receptor Tom70 resulting in the activation of IRF-3. (14)

Orf9c

Orf9C had been shown to interact with proteins and modulates the NF-κB pathway and IκB kinases. (14)

Orf10

This 38 aa peptide seems unique to SARS-CoV-2, it has no homolog in SARS-CoV. (26). Its function is not yet determined but it doesn’t seem to be essential (27)

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