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P12473 (VP4_ROTRH) Reviewed, UniProtKB/Swiss-Prot

Last modified February 19, 2014. Version 99. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Outer capsid protein VP4
Alternative name(s):
Hemagglutinin

Cleaved into the following 2 chains:

  1. Outer capsid protein VP8*
  2. Outer capsid protein VP5*
OrganismRotavirus A (strain Monkey/United States/RRV/1980 G3-P5B[3]-I2-R2-C3-M3-A9-Nx-T3-E3-H6) (RV-A)
Taxonomic identifier10969 [NCBI]
Taxonomic lineageVirusesdsRNA virusesReoviridaeSedoreovirinaeRotavirusRotavirus A
Virus hostMacaca mulatta (Rhesus macaque) [TaxID: 9544]

Protein attributes

Sequence length776 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Spike-forming protein that mediates virion attachment to the host epithelial cell receptors and plays a major role in cell penetration, determination of host range restriction and virulence. It is subsequently lost, together with VP7, following virus entry into the host cell. Rotavirus attachment and entry into the host cell probably involves multiple sequential contacts between the outer capsid proteins VP4 and VP7, and the cell receptors. In sialic acid-dependent and/or integrin-dependent strains, VP4 seems to essentially target sialic acid and/or the integrin heterodimer ITGA2/ITGB1. Ref.9

Outer capsid protein VP5*: forms the spike "foot" and "body". Acts as a membrane permeabilization protein that mediates release of viral particles from endosomal compartments into the cytoplasm. In integrin-dependent strains, VP5* targets the integrin heterodimer ITGA2/ITGB1 for cell attachment. Ref.9

VP8* forms the head of the spikes. It is the viral hemagglutinin and an important target of neutralizing antibodies. In sialic acid-dependent strains, VP8* binds to host cell sialic acid, most probably a ganglioside, providing the initial contact. Ref.9

Subunit structure

VP4 is a homotrimer Potential. VP4 adopts a dimeric appearance above the capsid surface, while forming a trimeric base anchored inside the capsid layer. Only hints of the third molecule are observed above the capsid surface. It probably performs a series of molecular rearrangements during viral entry. Prior to trypsin cleavage, it is flexible. The priming trypsin cleavage triggers its rearrangement into rigid spikes with approximate two-fold symmetry of their protruding parts. After an unknown second triggering event, cleaved VP4 may undergo another rearrangement, in which two VP5* subunits fold back on themselves and join a third subunit to form a tightly associated trimer, shaped like a folded umbrella. VP5* is a homotrimer Potential. The trimer is coiled-coil stabilized by its C-terminus, however, its N-terminus, known as antigen domain or "body", seems to be flexible allowing it to self-associate either as a dimer or a trimer. The two- to three-fold reorganization and fold-back of VP5* may be linked to membrane penetration, by exposing its hydrophobic region. Interacts with host ITGA2 (via ITAG2 I-domain); this interaction occurs when ITGA2 is part of the integrin heterodimer ITGA2/ITGB1. Interacts with host integrin heterodimer ITGA4/ITGB1 and ITGA4/ITGB7. Ref.6 Ref.7 Ref.8

Subcellular location

Outer capsid protein VP4: Virion. Host rough endoplasmic reticulum Potential. Note: Immature double-layered particles assembled in the cytoplasm bud across the membrane of the endoplasmic reticulum, acquiring during this process a transient lipid membrane that is modified with the ER resident viral glycoproteins NSP4 and VP7; these enveloped particles also contain VP4. As the particles move towards the interior of the ER cisternae, the transient lipid membrane and the non-structural protein NSP4 are lost, while the virus surface proteins VP4 and VP7 rearrange to form the outermost virus protein layer, yielding mature infectious triple-layered particles.

Outer capsid protein VP8*: Virion. Note: Outer capsid protein.

Outer capsid protein VP5*: Virion. Note: Outer capsid protein.

Post-translational modification

Proteolytic cleavage by trypsin results in activation of VP4 functions and greatly increases infectivity. The penetration into the host cell is dependent on trypsin treatment of VP4. It produces two peptides, VP5* and VP8* that remain associated with the virion.

Miscellaneous

In group A rotaviruses, VP4 defines the P serotype.

This strain has been shown to be sialic acid-dependent, and integrin-dependent in cell culture conditions.

Sequence similarities

Belongs to the rotavirus VP4 family.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 776776Outer capsid protein VP4
PRO_0000041108
Chain1 – 231231Outer capsid protein VP8* Potential
PRO_0000041109
Chain248 – 776529Outer capsid protein VP5* Potential
PRO_0000041110

Regions

Region248 – 480233Antigen domain
Region308 – 3103DGE motif; interaction with ITGA2/ITGB1 heterodimer By similarity
Region389 – 40921Hydrophobic; possible role in virus entry into host cell Potential
Coiled coil484 – 51835 Potential
Compositional bias560 – 61657Ser-rich

Sites

Site231 – 2322Cleavage By similarity
Site247 – 2482Cleavage

Amino acid modifications

Glycosylation321N-linked (GlcNAc...); by host Potential
Glycosylation561N-linked (GlcNAc...); by host Potential
Glycosylation971N-linked (GlcNAc...); by host Potential
Glycosylation1111N-linked (GlcNAc...); by host Potential
Glycosylation1491N-linked (GlcNAc...); by host Potential
Glycosylation1831N-linked (GlcNAc...); by host Potential
Glycosylation1981N-linked (GlcNAc...); by host Potential
Disulfide bond203 ↔ 216 Potential
Disulfide bond318 ↔ 380 Potential

Natural variations

Natural variant109 – 1102EP → VA in strain: Isolate MMU-18006.
Natural variant1461T → S in strain: Isolate MMU-18006.
Natural variant1661A → G in strain: Isolate MMU-18006.
Natural variant235 – 2406PLALSA → LALSAS in strain: Isolate MMU-18006.
Natural variant244 – 2452IS → TY in strain: Isolate MMU-18006.

Experimental info

Sequence conflict731S → T in AAK52093. Ref.2
Sequence conflict1321N → Y in AAA47345. Ref.1
Sequence conflict3111D → E in AAK52093. Ref.2
Sequence conflict3381I → V in AAK52093. Ref.2
Sequence conflict4211F → L in AAK52093. Ref.2
Sequence conflict445 – 4462GG → SR in AAK52093. Ref.2
Sequence conflict4541Y → N in AAK52093. Ref.2
Sequence conflict4681L → F in AAK52093. Ref.2
Sequence conflict5191Y → D in AAK52093. Ref.2
Sequence conflict6901Y → F in AAK52093. Ref.2

Secondary structure

.............................................................................. 776
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P12473 [UniParc].

Last modified March 24, 2009. Version 2.
Checksum: C012EB9E3816A3F9

FASTA77686,554
        10         20         30         40         50         60 
MASLIYRQLL TNSYTVDLSD EIQEIGSTKT QNVTINLGPF AQTGYAPVNW GPGETNDSTT 

        70         80         90        100        110        120 
VEPVLDGPYQ PTSFNPPVDY WMLLAPTAAG VVVEGTNNTD RWLATILVEP NVTSETRSYT 

       130        140        150        160        170        180 
LFGTQEQITI ANASQTQWKF IDVVKTTQNG SYSQYGPLQS TPKLYAVMKH NGKIYTYNGE 

       190        200        210        220        230        240 
TPNVTTKYYS TTNYDSVNMT AFCDFYIIPR EEESTCTEYI NNGLPPIQNT RNIVPLALSA 

       250        260        270        280        290        300 
RNIISHRAQA NEDIVVSKTS LWKEMQYNRD ITIRFKFASS IVKSGGLGYK WSEISFKPAN 

       310        320        330        340        350        360 
YQYTYTRDGE DVTAHTTCSV NGMNDFNFNG GSLPTDFIIS RYEVIKENSY VYVDYWDDSQ 

       370        380        390        400        410        420 
AFRNMVYVRS LAANLNSVIC TGGDYSFALP VGQWPVMTGG AVSLHSAGVT LSTQFTDFVS 

       430        440        450        460        470        480 
FNSLRFRFRL TVEEPSFSIT RTRVGGLYGL PAAYPNNGKE YYEVAGRLSL ISLVPSNDDY 

       490        500        510        520        530        540 
QTPITNSVTV RQDLERQLGE LREEFNALSQ EIAMSQLIYL ALLPLDMFSM FSGIKSTIDA 

       550        560        570        580        590        600 
AKSMATSVMK KFKKSGLANS VSTLTDSLSD AASSISRGAS IRSVGSSASA WTDVSTQITD 

       610        620        630        640        650        660 
VSSSVSSIST QTSTISRRLR LKEMATQTEG MNFDDISAAV LKTKIDRSTQ ISPNTLPDIV 

       670        680        690        700        710        720 
TEASEKFIPN RAYRVINNDE VFEAGTDGRY FAYRVETFDE IPFDVQKFAD LVTDSPVISA 

       730        740        750        760        770 
IIDFKTLKNL NDNYGISRQQ AFNLLRSDPR VLREFINQDN PIIRNRIEQL IMQCRL 

« Hide

References

[1]"The rhesus rotavirus gene encoding protein VP3: location of amino acids involved in homologous and heterologous rotavirus neutralization and identification of a putative fusion region."
Mackow E.R., Shaw R.D., Matsui S.M., Vo P.T., Dang M.-N., Greenberg H.G.
Proc. Natl. Acad. Sci. U.S.A. 85:645-649(1988) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC RNA].
[2]"Proteolysis of monomeric recombinant rotavirus VP4 yields an oligomeric VP5* core."
Dormitzer P.R., Greenberg H.B., Harrison S.C.
J. Virol. 75:7339-7350(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]"Conservation of amino acid sequence of VP8 and cleavage region of 84-kDa outer capsid protein among rotaviruses recovered from asymptomatic neonatal infection."
Gorziglia M., Hoshino Y., Buckler-White A., Blumentals I., Glass R., Flores J., Kapikian A.Z., Chanock R.M.
Proc. Natl. Acad. Sci. U.S.A. 83:7039-7043(1986) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC RNA] OF 1-281.
Strain: Isolate MMU-18006.
[4]"Location of intrachain disulfide bonds in the VP5* and VP8* trypsin cleavage fragments of the rhesus rotavirus spike protein VP4."
Patton J.T., Hua J.J., Mansell E.A.
J. Virol. 67:4848-4855(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: DISULFIDE BONDS.
[5]"Cleavage of rhesus rotavirus VP4 after arginine 247 is essential for rotavirus-like particle-induced fusion from without."
Gilbert J.M., Greenberg H.B.
J. Virol. 72:5323-5327(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEOLYTIC CLEAVAGE SITE.
[6]"Rotaviruses interact with alpha4beta7 and alpha4beta1 integrins by binding the same integrin domains as natural ligands."
Graham K.L., Fleming F.E., Halasz P., Hewish M.J., Nagesha H.S., Holmes I.H., Takada Y., Coulson B.S.
J. Gen. Virol. 86:3397-3408(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH HUMAN INTEGRIN HETERODIMER ITGA4/ITGB1, INTERACTION WITH HUMAN INTEGRIN HETERODIMER ITGA4/ITGB7.
[7]"Alternative intermolecular contacts underlie the rotavirus VP5* two-to three-fold rearrangement."
Yoder J.D., Dormitzer P.R.
EMBO J. 25:1559-1568(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBUNIT.
[8]"Rotavirus spike protein VP5* binds alpha2beta1 integrin on the cell surface and competes with virus for cell binding and infectivity."
Graham K.L., Takada Y., Coulson B.S.
J. Gen. Virol. 87:1275-1283(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH SIMIAN INTEGRIN HETERODIMER ITGA2/ITGB1.
[9]"Effect of mutations in VP5 hydrophobic loops on rotavirus cell entry."
Kim I.S., Trask S.D., Babyonyshev M., Dormitzer P.R., Harrison S.C.
J. Virol. 84:6200-6207(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION OF VP5*.
[10]"The rhesus rotavirus VP4 sialic acid binding domain has a galectin fold with a novel carbohydrate binding site."
Dormitzer P.R., Sun Z.Y., Wagner G., Harrison S.C.
EMBO J. 21:885-897(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.4 ANGSTROMS) OF 62-224, STRUCTURE BY NMR OF 46-231.
[11]"Structural rearrangements in the membrane penetration protein of a non-enveloped virus."
Dormitzer P.R., Nason E.B., Prasad B.V.V., Harrison S.C.
Nature 430:1053-1058(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (3.2 ANGSTROMS) OF 248-525.
[12]"Rotavirus architecture at subnanometer resolution."
Li Z., Baker M.L., Jiang W., Estes M.K., Prasad B.V.V.
J. Virol. 83:1754-1766(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: STRUCTURE BY ELECTRON CRYOMICROSCOPY OF CAPSID SHELL.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
M18736 Genomic RNA. Translation: AAA47345.1.
AY033150 mRNA. Translation: AAK52093.1.
PIRVPXRRH. A31078.
VPXRRR. I25904.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1KQRX-ray1.40A62-224[»]
1KRINMR-A46-231[»]
1SLQX-ray3.20A/B/C/D/E/F248-525[»]
2B4HX-ray1.60A/B247-479[»]
2B4IX-ray2.00A/B/C247-479[»]
2P3IX-ray1.75A64-224[»]
2P3JX-ray1.90A64-224[»]
2P3KX-ray1.56A64-224[»]
3TB0X-ray2.00A64-224[»]
ModBaseSearch...
MobiDBSearch...

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Family and domain databases

Gene3D2.60.120.200. 1 hit.
InterProIPR008985. ConA-like_lec_gl_sf.
IPR013320. ConA-like_subgrp.
IPR000416. Haemagglutinin_VP4.
[Graphical view]
PfamPF00426. VP4_haemagglut. 1 hit.
[Graphical view]
SUPFAMSSF49899. SSF49899. 1 hit.
ProtoNetSearch...

Other

EvolutionaryTraceP12473.

Entry information

Entry nameVP4_ROTRH
AccessionPrimary (citable) accession number: P12473
Secondary accession number(s): P11201 expand/collapse secondary AC list , Q86214, Q86215, Q91HI9
Entry history
Integrated into UniProtKB/Swiss-Prot: October 1, 1989
Last sequence update: March 24, 2009
Last modified: February 19, 2014
This is version 99 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programViral Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references