VP4_ROTHW
ID VP4_ROTHW Reviewed; 775 AA.
AC P11193; Q05334; Q86202;
DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
DT 14-APR-2009, sequence version 3.
DT 23-FEB-2022, entry version 131.
DE RecName: Full=Outer capsid protein VP4 {ECO:0000255|HAMAP-Rule:MF_04132};
DE AltName: Full=Hemagglutinin {ECO:0000255|HAMAP-Rule:MF_04132};
DE Contains:
DE RecName: Full=Outer capsid protein VP8* {ECO:0000255|HAMAP-Rule:MF_04132};
DE Contains:
DE RecName: Full=Outer capsid protein VP5* {ECO:0000255|HAMAP-Rule:MF_04132};
OS Rotavirus A (strain RVA/Human/United States/Wa/1974/G1P1A[8]) (RV-A).
OC Viruses; Riboviria; Orthornavirae; Duplornaviricota; Resentoviricetes;
OC Reovirales; Reoviridae; Sedoreovirinae; Rotavirus; Rotavirus A.
OX NCBI_TaxID=10962;
OH NCBI_TaxID=9606; Homo sapiens (Human).
RN [1]
RP NUCLEOTIDE SEQUENCE.
RX PubMed=2839714; DOI=10.1128/jvi.62.8.2978-2984.1988;
RA Gorziglia M., Green K.Y., Nishikawa K., Taniguchi K., Jones R.W.,
RA Kapikian A.Z., Chanock R.M.;
RT "Sequence of the fourth gene of human rotaviruses recovered from
RT asymptomatic or symptomatic infections.";
RL J. Virol. 62:2978-2984(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RX PubMed=8389116; DOI=10.1007/bf01319006;
RA Kitamoto N., Mattion N.M., Estes M.K.;
RT "Alterations in the sequence of the gene 4 from a human rotavirus after
RT multiple passages in HepG2 liver cells.";
RL Arch. Virol. 130:179-185(1993).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RX PubMed=7530390; DOI=10.1016/s0042-6822(95)80029-8;
RA Padilla-Noriega L., Dunn S.J., Lopez S., Greenberg H.B., Arias C.F.;
RT "Identification of two independent neutralization domains on the VP4
RT trypsin cleavage products VP5* and VP8* of human rotavirus ST3.";
RL Virology 206:148-154(1995).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC RNA] OF 1-280.
RX PubMed=3018754; DOI=10.1073/pnas.83.18.7039;
RA Gorziglia M., Hoshino Y., Buckler-White A., Blumentals I., Glass R.,
RA Flores J., Kapikian A.Z., Chanock R.M.;
RT "Conservation of amino acid sequence of VP8 and cleavage region of 84-kDa
RT outer capsid protein among rotaviruses recovered from asymptomatic neonatal
RT infection.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:7039-7043(1986).
RN [5]
RP INTERACTION WITH HUMAN INTEGRIN HETERODIMER ITGA4/ITGB1 (OUTER CAPSID
RP VP5*), AND INTERACTION WITH HUMAN INTEGRIN HETERODIMER ITGA4/ITGB7 (OUTER
RP CAPSID PROTEIN VP5*).
RX PubMed=16298987; DOI=10.1099/vir.0.81102-0;
RA Graham K.L., Fleming F.E., Halasz P., Hewish M.J., Nagesha H.S.,
RA Holmes I.H., Takada Y., Coulson B.S.;
RT "Rotaviruses interact with alpha4beta7 and alpha4beta1 integrins by binding
RT the same integrin domains as natural ligands.";
RL J. Gen. Virol. 86:3397-3408(2005).
RN [6]
RP INTERACTION WITH HUMAN INTEGRIN HETERODIMER ITGA2/ITGB1 (OUTER CAPSID
RP PROTEIN VP5*).
RX PubMed=16603530; DOI=10.1099/vir.0.81580-0;
RA Graham K.L., Takada Y., Coulson B.S.;
RT "Rotavirus spike protein VP5* binds alpha2beta1 integrin on the cell
RT surface and competes with virus for cell binding and infectivity.";
RL J. Gen. Virol. 87:1275-1283(2006).
RN [7]
RP REVIEW.
RX PubMed=16575520; DOI=10.1007/s10719-006-5435-y;
RA Isa P., Arias C.F., Lopez S.;
RT "Role of sialic acids in rotavirus infection.";
RL Glycoconj. J. 23:27-37(2006).
RN [8]
RP FUNCTION (OUTER CAPSID PROTEIN VP8*).
RX PubMed=24501414; DOI=10.1128/jvi.03431-13;
RA Fleming F.E., Boehm R., Dang V.T., Holloway G., Haselhorst T., Madge P.D.,
RA Deveryshetty J., Yu X., Blanchard H., von Itzstein M., Coulson B.S.;
RT "Relative roles of GM1 ganglioside, N-acylneuraminic acids, and alpha2beta1
RT integrin in mediating rotavirus infection.";
RL J. Virol. 88:4558-4571(2014).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 64-223, AND FUNCTION (OUTER CAPSID
RP PROTEIN VP8*).
RX PubMed=17306299; DOI=10.1016/j.jmb.2007.01.028;
RA Blanchard H., Yu X., Coulson B.S., von Itzstein M.;
RT "Insight into host cell carbohydrate-recognition by human and porcine
RT rotavirus from crystal structures of the virion spike associated
RT carbohydrate-binding domain (VP8*).";
RL J. Mol. Biol. 367:1215-1226(2007).
CC -!- FUNCTION: [Outer capsid protein VP4]: Spike-forming protein that
CC mediates virion attachment to the host epithelial cell receptors and
CC plays a major role in cell penetration, determination of host range
CC restriction and virulence. Rotavirus attachment and entry into the host
CC cell probably involves multiple sequential contacts between the outer
CC capsid proteins VP4 and VP7, and the cell receptors. It is subsequently
CC lost, together with VP7, following virus entry into the host cell.
CC Following entry into the host cell, low intracellular or intravesicular
CC Ca(2+) concentration probably causes the calcium-stabilized VP7 trimers
CC to dissociate from the virion. This step is probably necessary for the
CC membrane-disrupting entry step and the release of VP4, which is locked
CC onto the virion by VP7. During the virus exit from the host cell, VP4
CC seems to be required to target the newly formed virions to the host
CC cell lipid rafts. {ECO:0000255|HAMAP-Rule:MF_04132}.
CC -!- FUNCTION: [Outer capsid protein VP5*]: Forms the spike 'foot' and
CC 'body' and acts as a membrane permeabilization protein that mediates
CC release of viral particles from endosomal compartments into the
CC cytoplasm. During entry, the part of VP5* that protrudes from the virus
CC folds back on itself and reorganizes from a local dimer to a trimer.
CC This reorganization may be linked to membrane penetration by exposing
CC VP5* hydrophobic region. In integrin-dependent strains, VP5* targets
CC the integrin heterodimer ITGA2/ITGB1 for cell attachment.
CC {ECO:0000255|HAMAP-Rule:MF_04132}.
CC -!- FUNCTION: VP8* Forms the head of the spikes and mediates the
CC recognition of specific host cell surface glycans (PubMed:17306299). It
CC is the viral hemagglutinin and an important target of neutralizing
CC antibodies (By similarity). In sialic acid-dependent strains, VP8*
CC binds to host cell sialic acid, most probably a ganglioside, providing
CC the initial contact (PubMed:24501414). In some other strains, VP8*
CC mediates the attachment to histo-blood group antigens (HBGAs) for viral
CC entry (By similarity). {ECO:0000255|HAMAP-Rule:MF_04132,
CC ECO:0000269|PubMed:17306299, ECO:0000269|PubMed:24501414}.
CC -!- SUBUNIT: [Outer capsid protein VP4]: Homotrimer. VP4 adopts a dimeric
CC appearance above the capsid surface, while forming a trimeric base
CC anchored inside the capsid layer. Only hints of the third molecule are
CC observed above the capsid surface. It probably performs a series of
CC molecular rearrangements during viral entry. Prior to trypsin cleavage,
CC it is flexible. The priming trypsin cleavage triggers its rearrangement
CC into rigid spikes with approximate two-fold symmetry of their
CC protruding parts. After an unknown second triggering event, cleaved VP4
CC may undergo another rearrangement, in which two VP5* subunits fold back
CC on themselves and join a third subunit to form a tightly associated
CC trimer, shaped like a folded umbrella. Interacts with VP6. Interacts
CC with VP7. {ECO:0000255|HAMAP-Rule:MF_04132}.
CC -!- SUBUNIT: [Outer capsid protein VP5*]: Homotrimer. The trimer is coiled-
CC coil stabilized by its C-terminus, however, its N-terminus, known as
CC antigen domain or 'body', seems to be flexible allowing it to self-
CC associate either as a dimer or a trimer (By similarity). Interacts with
CC host ITGA2 (via ITAG2 I-domain); this interaction occurs when ITGA2 is
CC part of the integrin heterodimer ITGA2/ITGB1 (PubMed:16603530).
CC Interacts with host integrin heterodimer ITGA4/ITGB1 and ITGA4/ITGB7
CC (PubMed:16298987). {ECO:0000255|HAMAP-Rule:MF_04132,
CC ECO:0000269|PubMed:16298987, ECO:0000269|PubMed:16603530}.
CC -!- SUBCELLULAR LOCATION: [Outer capsid protein VP4]: Virion
CC {ECO:0000255|HAMAP-Rule:MF_04132}. Host rough endoplasmic reticulum
CC {ECO:0000255|HAMAP-Rule:MF_04132}. Host cell membrane
CC {ECO:0000255|HAMAP-Rule:MF_04132}. Host cytoplasm, host cytoskeleton
CC {ECO:0000255|HAMAP-Rule:MF_04132}. Host endoplasmic reticulum-Golgi
CC intermediate compartment {ECO:0000255|HAMAP-Rule:MF_04132}. Note=The
CC outer layer contains 180 copies of VP4, grouped as 60 dimers. Immature
CC double-layered particles assembled in the cytoplasm bud across the
CC membrane of the endoplasmic reticulum, acquiring during this process a
CC transient lipid membrane that is modified with the ER resident viral
CC glycoproteins NSP4 and VP7; these enveloped particles also contain VP4.
CC As the particles move towards the interior of the ER cisternae, the
CC transient lipid membrane and the non-structural protein NSP4 are lost,
CC while the virus surface proteins VP4 and VP7 rearrange to form the
CC outermost virus protein layer, yielding mature infectious triple-
CC layered particles. VP4 also seems to associate with lipid rafts of the
CC host cell membrane probably for the exit of the virus from the infected
CC cell by an alternate pathway. {ECO:0000255|HAMAP-Rule:MF_04132}.
CC -!- SUBCELLULAR LOCATION: [Outer capsid protein VP8*]: Virion
CC {ECO:0000255|HAMAP-Rule:MF_04132}. Note=Outer capsid protein.
CC {ECO:0000255|HAMAP-Rule:MF_04132}.
CC -!- SUBCELLULAR LOCATION: [Outer capsid protein VP5*]: Virion
CC {ECO:0000255|HAMAP-Rule:MF_04132}. Note=Outer capsid protein.
CC {ECO:0000255|HAMAP-Rule:MF_04132}.
CC -!- DOMAIN: [Outer capsid protein VP4]: The VP4 spike is divided into a
CC foot, a stalk and body, and a head. {ECO:0000255|HAMAP-Rule:MF_04132}.
CC -!- PTM: [Outer capsid protein VP4]: Proteolytic cleavage by trypsin
CC results in activation of VP4 functions and greatly increases
CC infectivity. The penetration into the host cell is dependent on trypsin
CC treatment of VP4. It produces two peptides, VP5* and VP8* that remain
CC associated with the virion. Cleavage of VP4 by trypsin probably occurs
CC in vivo in the lumen of the intestine prior to infection of
CC enterocytes. Trypsin seems to be incorporated into the three-layered
CC viral particles but remains inactive as long as the viral outer capsid
CC is intact and would only be activated upon the solubilization of the
CC latter. {ECO:0000255|HAMAP-Rule:MF_04132}.
CC -!- MISCELLANEOUS: This strain probably does not use sialic acid to attach
CC to the host cell. {ECO:0000303|PubMed:16575520}.
CC -!- MISCELLANEOUS: In group A rotaviruses, VP4 defines the P serotype.
CC {ECO:0000255|HAMAP-Rule:MF_04132}.
CC -!- MISCELLANEOUS: Some rotavirus strains are neuraminidase-sensitive and
CC require sialic acid to attach to the cell surface. Some rotavirus
CC strains are integrin-dependent. Some rotavirus strains depend on
CC ganglioside for their entry into the host cell. Hsp70 also seems to be
CC involved in the entry of some strains. {ECO:0000255|HAMAP-
CC Rule:MF_04132}.
CC -!- SIMILARITY: Belongs to the rotavirus VP4 family. {ECO:0000255|HAMAP-
CC Rule:MF_04132}.
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DR EMBL; M96825; AAA47290.1; -; Genomic_RNA.
DR EMBL; L34161; AAA66953.1; -; Genomic_RNA.
DR PIR; A28839; VPXRW3.
DR PDB; 2DWR; X-ray; 2.50 A; A=65-223.
DR PDBsum; 2DWR; -.
DR SMR; P11193; -.
DR UniLectin; P11193; -.
DR PRIDE; P11193; -.
DR ABCD; P11193; 18 sequenced antibodies.
DR EvolutionaryTrace; P11193; -.
DR Proteomes; UP000006581; Genome.
DR GO; GO:0044172; C:host cell endoplasmic reticulum-Golgi intermediate compartment; IEA:UniProtKB-SubCell.
DR GO; GO:0020002; C:host cell plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0044168; C:host cell rough endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR GO; GO:0044163; C:host cytoskeleton; IEA:UniProtKB-SubCell.
DR GO; GO:0016020; C:membrane; IEA:UniProtKB-KW.
DR GO; GO:0039624; C:viral outer capsid; IEA:UniProtKB-UniRule.
DR GO; GO:0039665; P:permeabilization of host organelle membrane involved in viral entry into host cell; IEA:UniProtKB-UniRule.
DR GO; GO:0046813; P:receptor-mediated virion attachment to host cell; IDA:UniProtKB.
DR GO; GO:0099008; P:viral entry via permeabilization of inner membrane; IEA:UniProtKB-KW.
DR GO; GO:0019062; P:virion attachment to host cell; IEA:UniProtKB-UniRule.
DR HAMAP; MF_04132; Rota_A_VP4; 1.
DR HAMAP; MF_04125; Rota_VP4; 1.
DR InterPro; IPR013320; ConA-like_dom_sf.
DR InterPro; IPR042546; Rota_A_VP4.
DR InterPro; IPR035330; Rota_VP4_MID.
DR InterPro; IPR038017; Rota_VP4_MID_sf.
DR InterPro; IPR035329; VP4_helical.
DR Pfam; PF17477; Rota_VP4_MID; 1.
DR Pfam; PF17478; VP4_helical; 1.
DR SUPFAM; SSF111379; SSF111379; 1.
DR SUPFAM; SSF49899; SSF49899; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Capsid protein; Coiled coil; Disulfide bond; Hemagglutinin;
KW Host cell membrane; Host cytoplasm; Host cytoskeleton;
KW Host endoplasmic reticulum; Host membrane; Host-virus interaction;
KW Membrane; Outer capsid protein; Viral attachment to host cell;
KW Viral penetration into host cytoplasm;
KW Viral penetration via permeabilization of host membrane; Virion;
KW Virus entry into host cell.
FT CHAIN 1..775
FT /note="Outer capsid protein VP4"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT /id="PRO_0000041090"
FT CHAIN 1..230
FT /note="Outer capsid protein VP8*"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT /id="PRO_0000041091"
FT CHAIN 247..775
FT /note="Outer capsid protein VP5*"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT /id="PRO_0000041092"
FT REGION 65..223
FT /note="Spike head"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT REGION 247..479
FT /note="Antigen domain"
FT REGION 247..478
FT /note="Spike body and stalk (antigen domain)"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT REGION 307..309
FT /note="DGE motif; interaction with ITGA2/ITGB1 heterodimer"
FT /evidence="ECO:0000269|PubMed:16603530"
FT REGION 388..408
FT /note="Hydrophobic; possible role in virus entry into host
FT cell"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT REGION 509..775
FT /note="Spike foot"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT COILED 483..517
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT MOTIF 307..309
FT /note="DGE motif; interaction with ITGA2/ITGB1 heterodimer"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT MOTIF 447..449
FT /note="YGL motif; interaction with ITGA4"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT MOTIF 643..645
FT /note="KID motif; interaction with HSPA8"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT SITE 230..231
FT /note="Cleavage"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT SITE 240..241
FT /note="Cleavage"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT SITE 246..247
FT /note="Cleavage; associated with enhancement of
FT infectivity"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT DISULFID 317..379
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT CONFLICT 64
FT /note="I -> M (in Ref. 3; AAA66953)"
FT /evidence="ECO:0000305"
FT CONFLICT 100
FT /note="D -> E (in Ref. 4)"
FT /evidence="ECO:0000305"
FT CONFLICT 120
FT /note="T -> L (in Ref. 1)"
FT /evidence="ECO:0000305"
FT CONFLICT 265
FT /note="Q -> E (in Ref. 4)"
FT /evidence="ECO:0000305"
FT CONFLICT 331
FT /note="S -> F (in Ref. 3; AAA66953)"
FT /evidence="ECO:0000305"
FT CONFLICT 388
FT /note="I -> L (in Ref. 2; AAA47290)"
FT /evidence="ECO:0000305"
FT CONFLICT 525
FT /note="D -> G (in Ref. 2; AAA47290)"
FT /evidence="ECO:0000305"
FT CONFLICT 618
FT /note="F -> L (in Ref. 1)"
FT /evidence="ECO:0000305"
FT CONFLICT 749
FT /note="N -> K (in Ref. 1)"
FT /evidence="ECO:0000305"
FT CONFLICT 759
FT /note="N -> H (in Ref. 1)"
FT /evidence="ECO:0000305"
FT CONFLICT 774
FT /note="K -> R (in Ref. 1)"
FT /evidence="ECO:0000305"
FT STRAND 66..69
FT /evidence="ECO:0007829|PDB:2DWR"
FT STRAND 71..74
FT /evidence="ECO:0007829|PDB:2DWR"
FT STRAND 80..85
FT /evidence="ECO:0007829|PDB:2DWR"
FT STRAND 88..96
FT /evidence="ECO:0007829|PDB:2DWR"
FT STRAND 98..100
FT /evidence="ECO:0007829|PDB:2DWR"
FT STRAND 102..108
FT /evidence="ECO:0007829|PDB:2DWR"
FT STRAND 110..121
FT /evidence="ECO:0007829|PDB:2DWR"
FT STRAND 124..132
FT /evidence="ECO:0007829|PDB:2DWR"
FT STRAND 134..146
FT /evidence="ECO:0007829|PDB:2DWR"
FT STRAND 152..161
FT /evidence="ECO:0007829|PDB:2DWR"
FT STRAND 163..169
FT /evidence="ECO:0007829|PDB:2DWR"
FT STRAND 172..179
FT /evidence="ECO:0007829|PDB:2DWR"
FT STRAND 184..189
FT /evidence="ECO:0007829|PDB:2DWR"
FT STRAND 197..200
FT /evidence="ECO:0007829|PDB:2DWR"
FT STRAND 204..208
FT /evidence="ECO:0007829|PDB:2DWR"
FT HELIX 209..211
FT /evidence="ECO:0007829|PDB:2DWR"
FT HELIX 212..221
FT /evidence="ECO:0007829|PDB:2DWR"
SQ SEQUENCE 775 AA; 87697 MW; 1CE181B859F74FB0 CRC64;
MASLIYRQLL TNSYSVDLHD EIEQIGSEKT QNVTINPSPF AQTRYAPVNW GHGEINDSTT
VEPILDGPYQ PTTFTPPNDY WILINSNTNG VVYESTNNSD FWTAVVAIEP HVNPVDRQYT
IFGESKQFNV SNDSNKWKFL EMFRSSSQNE FYNRRTLTSD TRFVGILKYG GRVWTFHGET
PRATTDSSST ANLNNISITI HSEFYIIPRS QESKCNEYIN NGLPPIQNTR NVVPLPLSSR
SIQYKRAQVN EDIIVSKTSL WKEMQYNRDI IIRFKFGNSI VKMGGLGYKW SEISYKAANY
QYNYLRDGEQ VTAHTTCSVN GVNNFSYNGG SLPTDFGISR YEVIKENSYV YVDYWDDSKA
FRNMVYVRSL AANLNSVKCT GGSYNFSIPV GAWPVMNGGA VSLHFAGVTL STQFTDFVSL
NSLRFRFSLT VDEPPFSILR TRTVNLYGLP AANPNNGNEY YEISGRFSLI YLVPTNDDYQ
TPIMNSVTVR QDLERQLTDL REEFNSLSQE IAMAQLIDLA LLPLDMFSMF SGIKSTIDLT
KSMATSVMKK FRKSKLATSI SEMTNSLSDA ASSASRNVSI RSNLSAISNW TNVSNDVSNV
TNSLNDISTQ TSTISKKFRL KEMITQTEGM SFDDISAAVL KTKIDMSTQI GKNTLPDIVT
EASEKFIPKR SYRILKDDEV MEINTEGKFF AYKINTFDEV PFDVNKFAEL VTDSPVISAI
IDFKTLKNLN DNYGITRTEA LNLIKSNPNM LRNFINQNNP IIRNRIEQLI LQCKL
