ID   NSP4_ROTBU              Reviewed;         175 AA.
AC   P04513; P12477;
DT   13-AUG-1987, integrated into UniProtKB/Swiss-Prot.
DT   01-JAN-1990, sequence version 2.
DT   24-JAN-2024, entry version 113.
DE   RecName: Full=Non-structural glycoprotein 4 {ECO:0000255|HAMAP-Rule:MF_04091};
DE            Short=NSP4 {ECO:0000255|HAMAP-Rule:MF_04091};
DE   AltName: Full=NCVP5 {ECO:0000255|HAMAP-Rule:MF_04091};
DE   AltName: Full=NS28 {ECO:0000255|HAMAP-Rule:MF_04091};
OS   Rotavirus A (strain RVA/Cow/United Kingdom/UK/1975/G6P7[5]) (RV-A).
OC   Viruses; Riboviria; Orthornavirae; Duplornaviricota; Resentoviricetes;
OC   Reovirales; Sedoreoviridae; Rotavirus; Rotavirus A.
OX   NCBI_TaxID=10934;
OH   NCBI_TaxID=9913; Bos taurus (Bovine).
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RX   PubMed=6099939; DOI=10.1016/0168-1702(84)90011-x;
RA   Baybutt H.N., McCrae M.A.;
RT   "The molecular biology of rotaviruses. VII. Detailed structural analysis of
RT   gene 10 of bovine rotavirus.";
RL   Virus Res. 1:533-541(1984).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RX   PubMed=2998051; DOI=10.1016/0042-6822(85)90275-2;
RA   Ward C.W., Azad A.A., Dyall-Smith M.L.;
RT   "Structural homologies between RNA gene segments 10 and 11 from UK bovine,
RT   simian SA11, and human Wa rotaviruses.";
RL   Virology 144:328-336(1985).
RN   [3]
RP   SUBCELLULAR LOCATION, AND GLYCOSYLATION.
RX   PubMed=17035333; DOI=10.1128/jvi.01378-06;
RA   Bugarcic A., Taylor J.A.;
RT   "Rotavirus nonstructural glycoprotein NSP4 is secreted from the apical
RT   surfaces of polarized epithelial cells.";
RL   J. Virol. 80:12343-12349(2006).
CC   -!- FUNCTION: Plays an essential role in the virus replication cycle by
CC       acting as a viroporin. Creates a pore in the host reticulum endoplasmic
CC       and as a consequence releases Ca(2+) in the cytoplasm of infected cell.
CC       In turn, high levels of cytoplasmic calcium trigger membrane
CC       trafficking and transport of viral ER-associated proteins to
CC       viroplasms, sites of viral genome replication and immature particle
CC       assembly. {ECO:0000255|HAMAP-Rule:MF_04091}.
CC   -!- FUNCTION: The secreted form acts as an enterotoxin that causes
CC       phospholipase C-dependent elevation of the intracellular calcium
CC       concentration in host intestinal mucosa cells. Increased concentration
CC       of intracellular calcium disrupts the cytoskeleton and the tight
CC       junctions, raising the paracellular permeability. Potentiates chloride
CC       ion secretion through a calcium ion-dependent signaling pathway,
CC       inducing age-dependent diarrhea. To perform this enterotoxigenic role
CC       in vivo, NSP4 is released from infected enterocytes in a soluble form
CC       capable of diffusing within the intestinal lumen and interacting with
CC       host plasma membrane receptors on neighboring epithelial cells such as
CC       integrins ITGA1/ITGB1 and ITGA2/ITGB1. {ECO:0000255|HAMAP-
CC       Rule:MF_04091}.
CC   -!- SUBUNIT: Homotetramer. Interacts with the immature particle in the
CC       viroplasm. Interacts with host CAV1, early and late in infection.
CC       Interacts with host integrin ITGA1/ITGB1 heterodimer. Interacts with
CC       host integrin ITGA2/ITGB1 heterodimer. Interaction with microtubules
CC       blocks trafficking to the Golgi apparatus. {ECO:0000255|HAMAP-
CC       Rule:MF_04091}.
CC   -!- SUBCELLULAR LOCATION: Host rough endoplasmic reticulum membrane
CC       {ECO:0000255|HAMAP-Rule:MF_04091}; Single-pass type III membrane
CC       protein {ECO:0000255|HAMAP-Rule:MF_04091}. Host membrane, host caveola
CC       {ECO:0000255|HAMAP-Rule:MF_04091}; Single-pass type III membrane
CC       protein {ECO:0000255|HAMAP-Rule:MF_04091}. Secreted {ECO:0000255|HAMAP-
CC       Rule:MF_04091}. Note=NSP4 localizes also in vesicular structures which
CC       contain autophagosomal markers and associate with viroplasms in virus-
CC       infected cells. Additionally, a soluble form of glycosylated NSP4 is
CC       secreted despite retention of its transmembrane domain.
CC       {ECO:0000255|HAMAP-Rule:MF_04091}.
CC   -!- DOMAIN: A disordered 28 aa C-terminal domain is presented to the
CC       cytoplasm by each subunit of the tetrameric receptor.
CC   -!- DOMAIN: Binds 1 calcium ion per tetramer. {ECO:0000255|HAMAP-
CC       Rule:MF_04091}.
CC   -!- PTM: Mannosylated.
CC   -!- PTM: The N-glycosyl content is primarily Man(9)GlcNAc, with a small
CC       amount of Man(8)GlcNAc. {ECO:0000255|HAMAP-Rule:MF_04091}.
CC   -!- SIMILARITY: Belongs to the rotavirus NSP4 family. {ECO:0000255|HAMAP-
CC       Rule:MF_04091}.
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DR   EMBL; M21885; AAA47313.1; -; Genomic_RNA.
DR   EMBL; K03384; AAA47288.1; -; Genomic_RNA.
DR   PIR; A04141; VGXRBR.
DR   iPTMnet; P04513; -.
DR   Proteomes; UP000008657; Genome.
DR   GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR   GO; GO:0044155; C:host caveola; IEA:UniProtKB-SubCell.
DR   GO; GO:0044169; C:host cell rough endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0016020; C:membrane; IEA:UniProtKB-UniRule.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-UniRule.
DR   GO; GO:0005216; F:monoatomic ion channel activity; IEA:UniProtKB-KW.
DR   GO; GO:0090729; F:toxin activity; IEA:UniProtKB-UniRule.
DR   GO; GO:0039520; P:induction by virus of host autophagy; IEA:UniProtKB-KW.
DR   GO; GO:0051259; P:protein complex oligomerization; IEA:UniProtKB-KW.
DR   GO; GO:0039707; P:virus-mediated pore formation in host cell membrane; IEA:UniProtKB-KW.
DR   Gene3D; 1.20.5.430; -; 1.
DR   HAMAP; MF_04091; ROTA_NSP4; 1.
DR   InterPro; IPR002107; Rotavirus_NSP4.
DR   Pfam; PF01452; Rota_NSP4; 1.
DR   SUPFAM; SSF58030; Rotavirus nonstructural proteins; 1.
PE   1: Evidence at protein level;
KW   Activation of host autophagy by virus; Calcium; Enterotoxin; Glycoprotein;
KW   Host endoplasmic reticulum; Host membrane; Host-virus interaction;
KW   Ion channel; Ion transport; Membrane; Metal-binding; Secreted;
KW   Signal-anchor; Toxin; Transmembrane; Transmembrane helix; Transport;
KW   Viral ion channel; Virulence.
FT   CHAIN           1..175
FT                   /note="Non-structural glycoprotein 4"
FT                   /id="PRO_0000149623"
FT   TOPO_DOM        1..28
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04091"
FT   TRANSMEM        29..51
FT                   /note="Helical; Signal-anchor for type III membrane
FT                   protein"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04091"
FT   TOPO_DOM        52..175
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04091"
FT   BINDING         120
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04091"
FT   BINDING         123
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04091"
FT   CARBOHYD        8
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04091,
FT                   ECO:0000269|PubMed:17035333"
FT   CARBOHYD        18
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04091,
FT                   ECO:0000269|PubMed:17035333"
FT   CONFLICT        19
FT                   /note="S -> N (in Ref. 2; AAA47288)"
FT   CONFLICT        37
FT                   /note="V -> A (in Ref. 2; AAA47288)"
FT   CONFLICT        131
FT                   /note="H -> Y (in Ref. 2; AAA47288)"
FT   CONFLICT        136..140
FT                   /note="IRTVD -> VRSTG (in Ref. 2; AAA47288)"
FT   CONFLICT        161..163
FT                   /note="NGR -> SGK (in Ref. 2; AAA47288)"
SQ   SEQUENCE   175 AA;  20492 MW;  86584FDB806CF240 CRC64;
     MEKLTDLNYT LSVITLMNST LHTILEDPGM AYFPYIVSVL TVLFTLHKAS IPTMKIALKT
     SKCSYKVVKY CIVTIFNTLL KLAGYKEQIT TKDEIEKQMD RVVKEMRRQL EMIDKLTTRE
     IEQVELLKRI HDKLMIRTVD EIDMTKEINQ KNVRTLEEWE NGRNPYEPKE VTAAM
//