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57  structures 59  species 0  interactions 1920  sequences 5  architectures

Family: Alpha_E1_glycop (PF01589)

Summary: Alphavirus E1 glycoprotein

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "Alphavirus". More...

Alphavirus Edit Wikipedia article

In biology and immunology, an alphavirus belongs to the group IV Togaviridae family of viruses, according to the system of classification based on viral genome composition introduced by David Baltimore in 1971. Alphaviruses, like all other group IV viruses have a positive sense single stranded RNA genome. There are 30 alphaviruses able to infect various vertebrates such as humans, rodents, fish, birds, and larger mammals such as horses as well as invertebrates. Transmission between species and individuals occurs mainly via mosquitoes making the alphaviruses a contributor to the collection of Arboviruses – or Arthropod Borne Viruses. Alphaviruses particles are enveloped, have a 70 nm diameter, tend to be spherical (although slightly pleomorphic), and have a 40 nm isometric nucleocapsid.

Genome

Alpha_E1_glycop
PDB 1rer EBI.jpg
crystal structure of the homotrimer of fusion glycoprotein e1 from semliki forest virus.
Identifiers
Symbol Alpha_E1_glycop
Pfam PF01589
InterPro IPR002548
SCOP 1rer
SUPERFAMILY 1rer
TCDB 1.G
OPM superfamily 117
OPM protein 1rer
Alpha_E2_glycop
PDB 1z8y EBI.jpg
mapping the e2 glycoprotein of alphaviruses
Identifiers
Symbol Alpha_E2_glycop
Pfam PF00943
InterPro IPR000936
TCDB 1.G
OPM superfamily 117
OPM protein 2yew
Alpha_E3_glycop
Identifiers
Symbol Alpha_E3_glycop
Pfam PF01563
InterPro IPR002533
TCDB 1.G
OPM superfamily 117

The alphaviruses are small, spherical, enveloped viruses with a genome of a single positive sense strand RNA. The total genome length ranges between 11,000 and 12,000 nucleotides, and has a 5’ cap, and 3’ poly-A tail. The four non-structural protein genes are encoded in the 5′ two-thirds of the genome, while the three structural proteins are translated from a subgenomic mRNA colinear with the 3′ one-third of the genome.

There are two open reading frames (ORF’s) in the genome, non-structural and structural. The first is non structural and encodes proteins (nsP1–nsP4) necessary for transcription and replication of viral RNA. The second encodes three structural proteins: the core nucleocapsid protein C, and the envelope proteins P62 and E1 that associate as a heterodimer. The viral membrane-anchored surface glycoproteins are responsible for receptor recognition and entry into target cells through membrane fusion.

Structural proteins

The proteolytic maturation of P62 into E2 and E3 causes a change in the viral surface. Together the E1, E2, and sometimes E3, glycoprotein "spikes" form an E1/E2 dimer or an E1/E2/E3 trimer, where E2 extends from the centre to the vertices, E1 fills the space between the vertices, and E3, if present, is at the distal end of the spike.[1] Upon exposure of the virus to the acidity of the endosome, E1 dissociates from E2 to form an E1 homotrimer, which is necessary for the fusion step to drive the cellular and viral membranes together. The alphaviral glycoprotein E1 is a class II viral fusion protein, which is structurally different from the class I fusion proteins found in influenza virus and HIV. The structure of the Semliki Forest virus revealed a structure that is similar to that of flaviviral glycoprotein E, with three structural domains in the same primary sequence arrangement.[2] The E2 glycoprotein functions to interact with the nucleocapsid through its cytoplasmic domain, while its ectodomain is responsible for binding a cellular receptor. Most alphaviruses lose the peripheral protein E3, but in Semliki viruses it remains associated with the viral surface.

Non structural proteins

Four nonstructural proteins (nsP1-4) which are produced as a single polyprotein constitute the virus' replication machinery.[3] The processing of the polyprotein occurs in a highly regulated manner, with cleavage at the P2/3 junction influencing RNA template use during genome replication. This site is located at the base of a narrow cleft and is not readily accessible. Once cleaved nsP3 creates a ring structure that encircles nsP2. These two proteins have an extensive interface.

Mutations in nsP2 that produce noncytopathic viruses or a temperature sensitive phenotypes cluster at the P2/P3 interface region. P3 mutations opposite the location of the nsP2 noncytopathic mutations prevent efficient cleavage of P2/3. This in turn affects RNA infectivity altering viral RNA production levels.

Virology

The nucleocapsid, 40 nanometers in diameter, contains 240 copies of the capsid protein and has a T = 4 icosahedral symmetry. The E1 and E2 viral glycoproteins are embedded in the lipid bilayer. Single E1 and E2 molecules associate to form heterodimers. The E1-E2 heterodimers form one-to-one contacts between the E2 protein and the nucleocapsid monomers.

Replication occurs within the cytoplasm, and virions mature by budding through the plasma membrane, where virus-encoded surface glycoproteins E2 and E1 are assimilated.

These two glycoproteins are the targets of numerous serologic reactions and tests including neutralization and hemagglutination inhibition. The alphaviruses show various degrees of antigenic cross-reactivity in these reactions and this forms the basis for the seven antigenic complexes, 30 species and many subtypes and varieties. The E2 protein is the site of most neutralizing epitopes, while the E1 protein contains more conserved, cross-reactive epitopes.

Evolution

A study of this taxon suggests that this group of viruses had a marine origin - specifically the Southern Ocean - and that they have subsequently spread to both the Old and New World.[4]

There are three subgroups in this genus: the Semliki Forest virus subgroup (Semliki Forest, O'nyong-nyong and Ross River viruses); the eastern equine encephalitis virus subgroup (eastern equine encephalitis and Venezuelan equine encephalitis viruses) and the Sindbis virus subgroup.[5] Sindbis virus, geographically restricted to the Old World, is more closely related to the eastern equine encephalitis subgroup, which are New World viruses, than it is to the Semliki Forest virus subgroup which is also found in the Old World.

Taxonomy

The seven complexes are:

Barmah Forest virus complex
Barmah Forest virus
Eastern equine encephalitis complex
Eastern equine encephalitis virus (seven antigenic types)
Middelburg virus complex
Middelburg virus
Ndumu virus complex
Ndumu virus
Semliki Forest virus complex
Bebaru virus
Chikungunya virus
Mayaro virus
Subtype: Una virus
O’Nyong Nyong virus
Subtype: Igbo-Ora virus
Ross River virus
Subtype: Bebaru virus
Subtype: Getah virus
Subtype: Sagiyama virus
Semliki Forest virus
Subtype: Me Tri virus
Venezuelan equine encephalitis complex
Cabassou virus
Everglades virus
Mosso das Pedras virus
Mucambo virus
Paramana virus
Pixuna virus
Rio Negro virus
Trocara virus
Subtype: Bijou Bridge virus
Venezuelan equine encephalitis virus
Western equine encephalitis complex
Aura virus
Babanki virus
Kyzylagach virus
Sindbis virus
Ockelbo virus
Whataroa virus
Recombinants within this complex
Buggy Creek virus
Fort Morgan virus
Highlands J virus
Western equine encephalitis virus
Unclassified
Salmon pancreatic disease virus
Sleeping Disease virus
Southern elephant seal virus
Tonate virus

Notes

Barmah Forest virus is related to the Semliki Forest virus. Middelburg virus, although classified as a separate complex, may be a member of the Semliki Forest virus group.

It seems likely that the genus evolved in the Old World from an insect-borne plant virus.[6]

Sinbis virus may have originated in South America.[7] The equine encephalitis viruses and Sinbis viruses are related.

The Old World and New World viruses appears to have diverged between 2000 and 3000 years ago.[8] Divergence between the Venezuelan equine encephalitis virus and the eastern equine virus appears to be have been ~1400 years ago.[9]

The fish infecting clade appears to be basal to the other species.

The southern elephant seal virus appears to be related to the Sinbis clade.

Pathogenesis and immune response

Medically important alphaviruses
Virus Human Disease Vertebrate Reservoir Distribution
Barmah Forest virus Fever, malaise, rash, joint pain, muscle tenderness Humans Australia
Chikungunya virus Rash, arthritis Primates, humans Africa, India, SE Asia
Mayaro virus Rash, arthritis Primates, humans South America
O'nyong'nyong virus Rash, arthritis Primates, Humans Africa
Ross River virus Rash, arthritis Mammals, humans Australia, South Pacific
Semliki Forest virus Rash, arthritis Birds Africa
Sindbis virus Rash, arthritis Birds Europe, Africa, Australia
Una virus Rash, arthritis Primates, humans South America
Eastern equine encephalitis virus Encephalitis Birds Americas
Tonate virus Encephalitis Humans South America
Venezuelan equine encephalitis virus Encephalitis Rodents, horses Americas
Western equine encephalitis virus Encephalitis Birds, mammals North America

There are many alphaviruses distributed around the world with the ability to cause human disease. Infectious arthritis, encephalitis, rashes and fever being the most commonly observed. Larger mammals such as humans and horses are usually dead-end hosts or play a minor role in viral transmission, however in the case of Venezuelan equine encephalitis the virus is mainly amplified in horses. In most other cases the virus is maintained in nature in mosquitoes, rodents and birds.

Alphavirus infections are spread by insect vectors such as mosquitoes. Once a human is bitten by the infected mosquito, the virus can gain entry into the bloodstream, causing viremia. The alphavirus can also get into the CNS where it is able to grow and multiply within the neurones. This can lead to encephalitis, which can be fatal.

When an individual is infected with this particular virus, its immune system can play a role in clearing away the virus particles. Alphaviruses are able to cause the production of interferons. Antibodies and T cells are also involved. The neutralizing antibodies also play an important role to prevent further infection and spread.

Diagnosis, prevention, and control

Diagnoses is based on clinical samples from which the virus can be easily isolated and identified. There are no alphavirus vaccines currently available. Vector control with repellents, protective clothing, breeding site destruction, and spraying are the preventive measures of choice.

Research

Alphaviruses are of interest to gene therapy researchers, in particular the Ross River virus, Sindbis virus, Semliki Forest virus, and Venezuelan equine encephalitis virus have all been used to develop viral vectors for gene delivery. Of particular interest are the chimeric viruses that may be formed with alphaviral envelopes and retroviral capsids. Such chimeras are termed pseudotyped viruses. Alphaviral envelope pseudotypes of retroviruses or lentiviruses are able to integrate the genes that they carry into the expansive range of potential host cells that are recognized and infected by the alphaviral envelope proteins E2 and E1. The stable integration of viral genes is mediated by the retroviral interiors of these vectors. There are limitations to the use of alphaviruses in the field of gene therapy due to their lack of targeting, however, through the introduction of variable antibody domains in a non-conserved loop in the structure of E2, specific populations of cells have been targeted. Furthermore, the use of whole alphaviruses for gene therapy is of limited efficacy both because several internal alphaviral proteins are involved in the induction of apoptosis upon infection and also because the alphaviral capsid mediates only the transient introduction of mRNA into host cells. Neither of these limitations extend to alphaviral envelope pseudotypes of retroviruses or lentiviruses. However, the expression of Sindbis virus envelopes may lead to apoptosis, and their introduction into host cells upon infection by Sindbis virus envelope pseudotyped retroviruses may also lead to cell death. The toxicity of Sindbis viral envelopes may be the cause of the very low production titers realized from packaging cells constructed to produce Sindbis pseudotypes. Another branch of research involving alphaviruses is in vaccination. Alphaviruses are apt to be engineered to create replicon vectors which efficiently induce humoral and T-cell immune responses. They could therefore be used to vaccinate against viral, bacterial, protozoan, and tumor antigens.

See also

Sources

References

  1. ^ Vénien-Bryan C, Fuller SD (February 1994). "The organization of the spike complex of Semliki Forest virus". J. Mol. Biol. 236 (2): 572–83. doi:10.1006/jmbi.1994.1166. PMID 8107141. 
  2. ^ Lescar J, Roussel A, Wien MW, Navaza J, Fuller SD, Wengler G, Wengler G, Rey FA (April 2001). "The Fusion glycoprotein shell of Semliki Forest virus: an icosahedral assembly primed for fusogenic activation at endosomal pH". Cell 105 (1): 137–48. doi:10.1016/S0092-8674(01)00303-8. PMID 11301009. 
  3. ^ Shin G, Yost SA, Miller MT, Elrod EJ, Grakoui A, Marcotrigiano J (2012) Structural and functional insights into alphavirus polyprotein processing and pathogenesis. Proc Natl Acad Sci USA
  4. ^ Forrester NL, Palacios G, Tesh RB, Savji N, Guzman H, Sherman M, Weaver SC, Lipkin WI (December 2011). "Genome scale phylogeny of the Alphavirus genus suggests a marine origin". J Virol 86 (5): 2729–38. doi:10.1128/JVI.05591-11. PMID 22190718. 
  5. ^ Levinson RS, Strauss JH, Strauss EG (1990) Complete sequence of the genomic RNA of O'nyong-nyong virus and its use in the construction of alphavirus phylogenetic trees. Virology 175(1):110-123
  6. ^ Powers AM, Brault AC, Shirako Y, Strauss EG, Kang W, Strauss JH, Weaver SC (November 2001). "Evolutionary relationships and systematics of the alphaviruses". J. Virol. 75 (21): 10118–31. doi:10.1128/JVI.75.21.10118-10131.2001. PMC 114586. PMID 11581380. 
  7. ^ Lundström JO, Pfeffer M (November 2010). "Phylogeographic structure and evolutionary history of Sindbis virus". Vector Borne Zoonotic Dis. 10 (9): 889–907. doi:10.1089/vbz.2009.0069. PMID 20420530. 
  8. ^ Weaver SC, Hagenbaugh A, Bellew LA, Netesov SV, Volchkov VE, Chang GJ, Clarke DK, Gousset L, Scott TW, Trent DW (November 1993). "A comparison of the nucleotide sequences of eastern and western equine encephalomyelitis viruses with those of other alphaviruses and related RNA viruses". Virology 197 (1): 375–90. doi:10.1006/viro.1993.1599. PMID 8105605. 
  9. ^ Weaver SC, Rico-Hesse R, Scott TW (1992). "Genetic diversity and slow rates of evolution in New World alphaviruses". Curr. Top. Microbiol. Immunol. 176: 99–117. PMID 1318187. 

External links

This article incorporates text from the public domain Pfam and InterPro IPR000936

This article incorporates text from the public domain Pfam and InterPro IPR002533

This article incorporates text from the public domain Pfam and InterPro IPR002548

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Alphavirus E1 glycoprotein Provide feedback

E1 forms a heterodimer with E2 PF00943. The virus spikes are made up of 80 trimers of these heterodimers (sindbis virus) [2].

Literature references

  1. Cheng RH, Kuhn RJ, Olson NH, Rossmann MG, Choi HK, Smith TJ, Baker TS; , Cell 1995;80:621-630.: Nucleocapsid and glycoprotein organization in an enveloped virus. PUBMED:7867069 EPMC:7867069

  2. Carleton M, Lee H, Mulvey M, Brown DT; , J Virol 1997;71:1558-1566.: Role of glycoprotein PE2 in formation and maturation of the Sindbis virus spike. PUBMED:8995682 EPMC:8995682


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR002548

Alphaviruses are enveloped RNA viruses that use arthropods such as mosquitoes for transmission to their vertebrate hosts, and include Semliki Forest and Sindbis viruses [PUBMED:15378043]. Alphaviruses consist of three structural proteins: the core nucleocapsid protein C, and the envelope proteins P62 and E1 that associate as a heterodimer. The viral membrane-anchored surface glycoproteins are responsible for receptor recognition and entry into target cells through membrane fusion. The proteolytic maturation of P62 into E2 (INTERPRO) and E3 (INTERPRO) causes a change in the viral surface. Together the E1, E2, and sometimes E3, glycoprotein "spikes" form an E1/E2 dimer or an E1/E2/E3 trimer, where E2 extends from the centre to the vertices, E1 fills the space between the vertices, and E3, if present, is at the distal end of the spike [PUBMED:8107141]. Upon exposure of the virus to the acidity of the endosome, E1 dissociates from E2 to form an E1 homotrimer, which is necessary for the fusion step to drive the cellular and viral membranes together. The alphaviral glycoprotein E1 is a class II viral fusion protein, which is structurally different from the class I fusion proteins found in influenza virus and HIV. The structure of the Semliki Forest virus revealed a structure that is similar to that of flaviviral glycoprotein E, with three structural domains in the same primary sequence arrangement [PUBMED:11301009]. This entry represents all three domains of the alphaviral E1 glycoprotein.

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan Viral_gly_cn_dm (CL0543), which has the following description:

Flavivirus and alpha virus glycoprotein E/E1 consists of three domains. A dimerisation domain, a central domain and an immunoglobulin-like domain. The dimerisation and central domains are intertwined [1-3].

The clan contains the following 2 members:

Alpha_E1_glycop Flavi_glycoprot

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...

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External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

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Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

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Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Pfam-B_587 (release 4.1)
Previous IDs: none
Type: Family
Author: Bateman A
Number in seed: 17
Number in full: 1920
Average length of the domain: 247.60 aa
Average identity of full alignment: 48 %
Average coverage of the sequence by the domain: 50.15 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 25.0 25.0
Trusted cut-off 25.3 27.0
Noise cut-off 18.2 24.6
Model length: 502
Family (HMM) version: 11
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Species distribution

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Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Alpha_E1_glycop domain has been found. There are 57 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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