Cell cycle effects[edit]
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[edit]
The N protein is involved in viral pathogenesis via its effects on components of the immune system. In SARS-CoV,[3][15][16] MERS-CoV,[17] and SARS-CoV-2,[18] N has been reported as suppressing interferon responses.
The structures of N proteins from different coronaviruses, particularly the C-terminal domains, appear to be well conserved.[2][6] Similarities between the structure and topology of the N proteins of coronaviruses and arterivirusessuggest 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.[6] A separate study of SARS-CoV-2 sequences identified at least one site in the N protein under positive selection.[19]
https://en.wikipedia.org/wiki/Coronavirus_nucleocapsid_protein
Intragenic complementation[edit]
Multiple copies of a polypeptide encoded by a gene often can form an aggregate referred to as a multimer. When a multimer is formed from polypeptides produced by two different mutant alleles of a particular gene, the mixed multimer may exhibit greater functional activity than the unmixed multimers formed by each of the mutants alone. When a mixed multimer displays increased functionality relative to the unmixed multimers, the phenomenon is referred to as intragenic complementation.
NS5A protein is a multimer, a dimer in this case, and intragenic complementation of replication-defective NS5A alleles has been demonstrated by Fridell et al.[10] On the bases of pairwise complementation tests between different NS5A mutant alleles, they identified three complementation groups that were considered to define three distinct and genetically separable functions of NS5A in RNA replication.
Mutations[edit]
Variants of SARS-CoV-2 As well as having eight mutations (four of these synonymous genetic mutations) in its open reading frames (ORF1a and ORF1b) – one of which is a set of deletions – Gamma has 10 defining mutations in its spike protein, including N501Y and E484K. It also has two mutations – one an insertion – in its ORF8 region and one in its N region.[5][23]
Descendant and sublineages[edit]
Coronavirus lineage B.1.1.28 has originated four known lineages classified as variant of interest (VOI) or variant of concern (VOC): lineages P.1, P.2, P.3and P.4.
Lineage P.2 (B.1.1.28.2, Zeta variant), first detected in October 2020 in the state of Rio de Janeiro, Brazil, only shares one mutation of concern with P.1, which is the E484K.[24] The other P.2 mutations are without concern and rarely found for other variants. The five P.2-specific mutations are: E484K in S-gene, A119S in N-gene, 5’UTR C100U, plus L3468V and synC11824U in ORF1ab-gene. Other mutations commonly found in P.2 are: 3’UTR C29754U, F120F (synC28253U) in ORF8, M234I in the N-gene, plus L3930F and synA12964G in ORF1ab.[25]
Lineage P.3 (Theta variant) was first identified in the Philippines on 18 February 2021 when two mutations of concern were detected in Central Visayas.[26]
The remaining B.1.1.28 derivative virus is lineage P.4. Although researchers have not identified its precise origin, it was first sequenced in Itirapina, Brazil, and was already circulating in various municipalities in the state of São Paulo of the same country. It carries a mutation of concern in the spike protein called L452R which is also present in lineage B.1.617 (Delta and Kappa variants) detected in India, Epsilon variant (lineages B.1.427 and B.1.429) from California, United States.[27][28] The branch of this lineage is P.4.1 (VUI-NP13L)—suspected to have arisen in Goiás, Brazil, around June–July 2020— also rapidly spread to the southeast of the country, where for example Taquara had its first genome sequence, and to the northeast of the nation. It was detected internationally, with reported cases in Japan, Netherlands and England. The P.4.1 has V1176F and D614G mutations in spike protein.[29]
Defining mutations in Gamma variantshow
https://en.wikipedia.org/wiki/SARS-CoV-2_Gamma_variant
Influenza hemagglutinin (HA) or haemagglutinin[p] (British English) is a homotrimeric glycoprotein found on the surface of influenza viruses and is integral to its infectivity.
Hemagglutinin is a Class I Fusion Protein, having multifunctional activity as both an attachment factor and membrane fusion protein. Therefore, HA is responsible for binding Influenza virus to sialic acid on the surface of target cells, such as cells in the upper respiratory tract or erythrocytes,[1] causing as a result the internalization of the virus.[2] Secondarily, HA is responsible for the fusion of the viral envelope with the late endosomal membrane once exposed to low pH (5.0-5.5).[3]
The name "hemagglutinin" comes from the protein's ability to cause red blood cells (erythrocytes) to clump together ("agglutinate") in vitro.[4]
https://en.wikipedia.org/wiki/Hemagglutinin_(influenza)
Human influenza hemagglutinin (HA) is a surface glycoprotein required for the infectivity of the human influenza virus. The HA tag is derived from the HA-molecule corresponding to amino acids 98-106. It has been extensively used as a general epitope tag in expression vectors. Many recombinant proteinshave been engineered to express the HA tag, which does not appear to interfere with the bioactivity or the biodistribution of the recombinant protein. This tag facilitates the detection, isolation, and purification of the protein of interest.[1]
The HA tag is not suitable for detection or purification of proteins from apoptotic cells since it is cleaved by Caspase-3 and / or Caspase-7 after its sequence DVPD, causing it to lose its immunoreactivity.[2] Labeling of endogenous proteins with HA-tag using CRISPR was recently accomplished in-vivo in differentiated neurons.[3]
https://en.wikipedia.org/wiki/HA-tag
Viral matrix proteins are structural proteins linking the viral envelope with the virus core. They play a crucial role in virus assembly, and interact with the RNP complex as well as with the viral membrane. They are found in many enveloped viruses including paramyxoviruses, orthomyxoviruses,[1] herpesviruses, retroviruses, filoviruses and other groups.
An example is the M1 protein of the influenza virus, showing affinity to the glycoproteins inserted in the host cell membrane on one side and affinity for the RNP complex molecules on the other side, which allows formation at the membrane of a complex made of the viral ribonucleoprotein at the inner side indirectly connected to the viral glycoproteins protruding from the membrane. This assembly complex will now bud out of the cell as new mature viruses.
Viral matrix proteins, like many other viral proteins, can exert different functions during the course of the infection. For example, in rhabdoviruses, binding of M proteins to nucleocapsids is accountable for the formation of its “bullet” shaped virions.
In herpesviruses, the viral matrix is usually called viral tegument and contains many proteins involved in viral entry, early gene expression and immune evasion.
https://en.wikipedia.org/wiki/Viral_matrix_protein
In molecular biology, VP40 is the name of a viral matrix protein. Most commonly it is found in the Ebola virus (EBOV),[1] a type of non-segmented, negative-strand RNA virus. Ebola virus causes a severe and often fatal haemorrhagic fever in humans, known as Ebola virus disease. The virus matrix protein VP40 is a major structural protein that plays a central role in virus assembly and budding at the plasma membraneof infected cells. VP40 proteins work by associating with cellular membranes, interacting with the cytoplasmic tails of glycoproteins and binding to the ribonucleoprotein complex.[citation needed]
https://en.wikipedia.org/wiki/VP40
Ebola viral protein 24 (eVP24) is considered a multifunctional secondary matrix protein present in viral particles.[1] The broad roles eVP24 performs involve the formation of fully functional and infectious viral particles, promotion of filamentous nucleocapsid formation, mediation of host responses to infection, and suppression of the host innate immune system. It has been noted that eVP24 function can overlap with that of two other viral proteins; eVP40 matrix protein which functions in virus budding, and eVP35 which is also associated with immune suppression.[2][3]
https://en.wikipedia.org/wiki/Ebola_viral_protein_24
p24 is a component of the HIV particle capsid. There are approximately 2000 molecules per virus particle, or at a molecule weight of 24 kDa, about 104 virus particles per picogram of p24. The onset of symptoms of AIDScorrelates with a reduction in the number of CD4+ T cells and increased levels of virus and p24 in the blood.[1] It is a component of the gag polyprotein.
https://en.wikipedia.org/wiki/P24_capsid_protein
HIV-1 protease (PR) is a retroviral aspartyl protease (retropepsin), an enzyme involved with peptide bondhydrolysis in retroviruses, that is essential for the life-cycle of HIV, the retrovirus that causes AIDS.[1][2] HIV protease cleaves newly synthesized polyproteins (namely, Gag and Gag-Pol[3]) at nine cleavage sites to create the mature protein components of an HIV virion, the infectious form of a virus outside of the host cell.[4] Without effective HIV protease, HIV virions remain uninfectious.[5][6]
| HIV-1 Protease (Retropepsin) | |
|---|---|
 HIV-1 protease dimer in white and grey, with peptide substrate in black and active siteaspartate side chains in red. (PDB: 1KJF) |
https://en.wikipedia.org/wiki/HIV-1_protease
Viral infectivity factor, or Vif, is an accessory protein found in HIV and other lentiviruses. Its role is to disrupt the antiviral activity of the human enzyme APOBEC (specifically APOBEC3G, "A3G" in short) by targeting it for ubiquitination and cellular degradation. APOBEC is a cytidine deaminase enzyme that mutates viral nucleic acids.
Vif is a 23-kilodalton protein that is essential for viral replication. Vif inhibits the cellular protein, APOBEC3G, from entering the virion during budding from a host cell by targeting it for proteasomal degradation. Vif binds to A3G as well as the cellular Cullin5 E3 Ubiquitin Ligase (ELOB-ELOC-CUL5) and a CBFB cofactor so that the ligase can be hijacked to tag A3G for degradation.[2] The crystal Structure of the HIV Vif BC-box in Complex with Human Elongin B and Elongin C was solved in 2008,[1] and the structure of the full Vif/E3 complex was solved in 2014.[3] In the absence of Vif, APOBEC3G causes hypermutation of the viral genome, rendering it dead-on-arrival at the next host cell. APOBEC3G is thus a host defence to retroviral infection which HIV-1 has overcome by the acquisition of Vif. Targeting Vif has been suggested as a strategy for future HIV drug therapies.[4]
Vif was considered as a phosphoprotein and phosphorylation seemed to be required for viral infectivity.[5][6]But recent studies with the use of metabolic labelling demonstrated that serine/threonine phosphorylation of Vif and A3G is not required for the interaction of Vif with A3G for Vif dependent degradation of A3G and the antiviral activity of A3G.[7]
Vif was considered as a phosphoprotein and phosphorylation seemed to be required for viral infectivity.[5][6]But recent studies with the use of metabolic labelling demonstrated that serine/threonine phosphorylation of Vif and A3G is not required for the interaction of Vif with A3G for Vif dependent degradation of A3G and the antiviral activity of A3G.[7]
In other species[edit]
Vif has been found in other Lentiviruses, including the Simian immunodeficiency virus (SIV), Feline immunodeficiency virus (FIV; Pfam PF05851), Visna virus (MVV) and Caprine arthritis encephalitis virus (Pfam PF07401).[8][9] The mamallian APOBEC3 enzymes are in an arms race with Vifs found in those viruses, actively evolving and diversifying to escape inactivation. Some Vifs use CYPA instead of CBFB.[10][11][12]
https://en.wikipedia.org/wiki/Viral_infectivity_factor
Vpu is an accessory protein that in HIV is encoded by the vpu gene. Vpu stands for "Viral Protein U". The Vpu protein acts in the degradation of CD4 in the endoplasmic reticulum and in the enhancement of virionrelease from the plasma membrane of infected cells.[1] Vpu induces the degradation of the CD4 viral receptor and therefore participates in the general downregulation of CD4 expression during the course of HIV infection. Vpu-mediated CD4 degradation is thought to prevent CD4-Env binding in the endoplasmic reticulum in order to facilitate proper Env assembly into virions.[2] It is found in the membranes of infected cells, but not the virus particles themselves.
The Vpu gene is found exclusively in HIV-1 and some HIV-1-related simian immunodeficiency virus (SIV) isolates, such as SIVcpz, SIVgsn, and SIVmon, but not in HIV-2 or the majority of SIV isolates.[3] Structural similarities between Vpu and another small viral protein, M2, encoded by influenza A virus were first noted soon after the discovery of Vpu. Since then, Vpu has been shown to form cation-selective ion channels when expressed in Xenopus oocytes or mammalian cells and also when purified and reconstituted into planar lipid bilayers.[4] Vpu also permeabilizes membranes of bacteria and mammalian cells to small molecules.[5]Therefore, it is considered a member of the Viroporins family.[6]
| Vpu | |
|---|---|
 structure of the channel-forming trans-membrane domain of virus protein "u" (vpu) from HIV-1 |
https://en.wikipedia.org/wiki/Vpu_protein
Vpx is a virion-associated protein encoded by human immunodeficiency virus type 2 HIV-2 and most simian immunodeficiency virus (SIV) strains, but that is absent from HIV-1.[1] It is similar in structure to the protein Vpr that is carried by SIV and HIV-2 as well as HIV-1.[2] Vpx is one of five accessory proteins (Vif, Vpx, Vpr, Vpu, and Nef) carried by lentiviruses that enhances viral replication by inhibiting host antiviral factors.[2]
Vpx enhances HIV-2 replication in humans by counteracting the host factor SAMHD1.[3] SAMHD1 is a host factor found in human myeloid cells, such as dendritic cells and macrophages, that restricts HIV-1 replication by depleting the cytoplasmic pool of deoxynucleoside triphosphates needed for viral DNA production.[4]SAMHD1 does not, however, restrict HIV-2 replication in myeloid cells due to the presence of viral Vpx. Vpx counteracts restriction by inducing the ubiquitin-proteasome-dependent degradation of SAMHD1.[3] Vpx-mediated degradation of SAMHD1 therefore decreases deoxynucleoside triphosphate hydrolysis, thereby increasing the availability of dNTPs for viral reverse transcription in the cytoplasm. It has been postulated that SAMHD1 degradation is required for HIV-2 replication because the HIV-2 reverse transcriptase (RT) is less active than the HIV-1 RT, which would be the reason for the absence of Vpx from HIV-1.[2] Because Vpx is required for HIV-2 reverse transcription and the early stages of the viral life cycle, it is packaged into virions in significant amounts.[5][6]
Vpx is also involved in the nuclear import of the HIV-2/SIV genomes and associated proteins,[7] but the specific mechanisms and interactions are currently unknown. Although Vpr and Vpx are similar in size (both are ~100 amino acids with 20-25% sequence similarity) and structure (both are predicted to have similar tertiary structure with three major helices), they serve very different roles in viral replication.[2] Vpx targets a host restriction factor for proteasomal degradation, while Vpr arrests the host cell cycle in the G2 phase.[2] However, they are both involved in the import of the viral preintegration complex into the host nucleus.[7]
https://en.wikipedia.org/wiki/Vpx
The gag-onc fusion protein[1] is a general term for a fusion protein formed from a group-specific antigen ('gag') gene and that of an oncogene ('onc'), a gene that plays a role in the development of a cancer. The name is also written as Gag-v-Onc, with "v" indicating that the Onc sequence resides in a viral genome.[1] Onc is a generic placeholder for a given specific oncogene, such as C-jun. (In the case of a fusion with C-jun, the resulting "gag-jun" protein is known alternatively as p65).[2]
https://en.wikipedia.org/wiki/Gag-onc_fusion_protein
The murine leukemia viruses (MLVs or MuLVs) are retroviruses named for their ability to cause cancer in murine(mouse) hosts. Some MLVs may infect other vertebrates. MLVs include both exogenous and endogenous viruses. Replicating MLVs have a positive sense, single-stranded RNA (ssRNA) genome that replicates through a DNA intermediate via the process of reverse transcription.
https://en.wikipedia.org/wiki/Murine_leukemia_virus
Rous sarcoma virus (RSV) (/raÊŠs/) is a retrovirus and is the first oncovirus to have been described. It causes sarcoma in chickens.
As with all retroviruses, it reverse transcribes its RNA genome into cDNA before integration into the host DNA.
https://en.wikipedia.org/wiki/Rous_sarcoma_virus
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.[1][2]
https://en.wikipedia.org/wiki/NS1_influenza_protein
Minor capsid protein VP2 and minor capsid protein VP3 are viral proteins that are components of the polyomavirus capsid. Polyomavirus capsids are composed of three proteins; the major component is major capsid protein VP1, which self-assembles into pentamers that in turn self-assemble into enclosed icosahedral structures. The minor components are VP2 and VP3, which bind in the interior of the capsid.[1][2][3]
https://en.wikipedia.org/wiki/Minor_capsid_proteins_VP2_and_VP3
Major capsid protein VP1 is a viral protein that is the main component of the polyomavirus capsid. VP1 monomers are generally around 350 amino acids long and are capable of self-assembly into an icosahedralstructure consisting of 360 VP1 molecules organized into 72 pentamers. VP1 molecules possess a surface binding site that interacts with sialic acids attached to glycans, including some gangliosides, on the surfaces of cells to initiate the process of viral infection. The VP1 protein, along with capsid components VP2 and VP3, is expressed from the "late region" of the circular viral genome.[1][2][3]
https://en.wikipedia.org/wiki/Major_capsid_protein_VP1
The Epstein–Barr virus nuclear antigen 3 (EBNA-3) is a family of viral proteins associated with the Epstein–Barr virus. A typical EBV genome contains three such proteins:[1]
- EBNA-3A (P12977, EBNA-3; BLRF3-BERF1)
- EBNA-3B (P03203, EBNA-4; BERF2A-BERF2B)
- EBNA-3C (P03204, EBNA-6, EBNA-4B; BERF3-BERF4)
These genes also bind the host RBP-Jκ protein.[2]
EBNA-3C can recruit a ubiquitin ligase and has been shown to target cell-cycle regulators such as retinoblastoma protein (pRb).[3][4]
https://en.wikipedia.org/wiki/Epstein–Barr_virus_nuclear_antigen_3
Epstein–Barr virus latent membrane protein 1 (LMP1) is an Epstein–Barr virus (EBV) protein that regulates its own expression and the expression of human genes.[1] It has a molecular weight of approximately 63 kDa, and its expression induces many of the changes associated with EBV infections and activation of primary B cells.[2] LMP1 is the best-documented oncoprotein of the EBV latent gene products, as it is expressed in most EBV-related human cancers[3] such as the various malignant Epstein-Barr virus-associated lymphoproliferative diseases.[4]
The structure of LMP1 consists of a short cytoplasmic terminal tail, six trans-membrane domains, and a long cytoplasmic C-terminus, which contains three activating domains: CTARt, CTAR2, and CTAR3. Each CTAR domain contains an amino acid sequence that serves as a recognition site for cellular adaptors to bind and trigger a series of signal transduction pathways that can lead to a change in gene expression.[5]
LMP-1 is a functional homologue of tumor necrosis factor[6] and mediates signaling through the nuclear factor-κB pathway, mimicking CD40 receptor signaling.[1][3]
It is often found in the malignant Reed–Sternberg cells of Hodgkin lymphoma,[7][8] the malignant B cells of EBV-associated B cell lymphatic cancers, and the malignant NK cells of NK/T cell lymphatic cancers.[4]
https://en.wikipedia.org/wiki/Epstein–Barr_virus_latent_membrane_protein_1
Vmw65, also known as VP16 or α-TIF (Trans Inducing Factor)[2] is a trans-acting protein that forms a complex with the host transcription factors Oct-1 and HCF to induce immediate early gene transcription in the herpes simplex viruses.[3][4]
VP16 is a strong transactivator [5] and is often used in Y2H systems as the activation domain of the system.[6]
https://en.wikipedia.org/wiki/Herpes_simplex_virus_protein_vmw65
Infected cell protein 47 also ICP-47 or ICP47 is a protein encoded by the viruses such as Herpes simplex virus and Cytomegalovirus that allows them to evade the human immune system's CD8 T-cell response by interfering with an infected cell's ability to show viral epitopes to T cells.[1] Its secondary structure shows three helices.
https://en.wikipedia.org/wiki/Infected_cell_protein_47
ICP8, the herpes simplex virus type-1 single-strand DNA-binding protein, is one of seven proteins encoded in the viral genome of HSV-1 that is required for HSV-1 DNA replication.[1] It is able to anneal to single-stranded DNA (ssDNA) as well as melt small fragments of double-stranded DNA (dsDNA);[1] its role is to destabilize duplex DNA during initiation of replication. It differs from helicases because it is ATP- and Mg2+-independent.[1] In cells infected with HSV-1, the DNA in those cells become colocalized with ICP8.
ICP8 is required in late gene transcription, and has found to be associated with cellular RNA polymerase II holoenzyme.[2]
https://en.wikipedia.org/wiki/ICP8
HHV Capsid Portal Protein, or HSV-1 UL-6 protein, is the protein which forms a cylindrical portal in the capsid of Herpes simplex virus (HSV-1). The protein is commonly referred to as the HSV-1 UL-6 protein because it is the transcription product of Herpes gene UL-6.
The Herpes viral DNA enters and exits the capsid via the capsid portal. The capsid portal is formed by twelve copies of portal protein arranged as a ring; the proteins contain a leucine zipper sequence of amino acidswhich allow them to adhere to each other.[1] Each icosahedral capsid contains a single portal, located in one vertex.[2][3]
The portal is formed during initial capsid assembly and interacts with scaffolding proteins that construct the procapsid.[4] [5] [6] When the capsid is nearly complete, the viral DNA enters the capsid (i.e., the DNA is encapsidated) by a mechanism involving the portal and a DNA-binding protein complex similar to bacteriophage terminase.[7] Multiple studies suggest an evolutionary relationship between Capsid Portal Protein and bacteriophage portal proteins.[2][7]
When a virus infects a cell, it is necessary for the viral DNA to be released from the capsid. The Herpes virus DNA exits through the capsid portal.[8]
The genetic sequence of HSV-1 gene UL-6 is conserved across the family Herpesviridae and this family of genes is known as the "Herpesvirus UL6-like" gene family.[9] "UL-6" is nomenclature meaning that the protein is genetically encoded by the sixth (6th) open reading frame found in the viral genome segment named "Unique-Long (UL)".
https://en.wikipedia.org/wiki/HHV_capsid_portal_protein
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