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P04512

- NSP4_ROTS1

UniProt

P04512 - NSP4_ROTS1

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Protein
Non-structural glycoprotein 4
Gene
N/A
Organism
Rotavirus A (strain SA11-Both G3-P5B[2]-I2-R2-C5-M5-A5-N2-T5-E2-H5) (RV-A) (Simian Agent 11 (strain Both))
Status
Reviewed - Annotation score: 5 out of 5 - Experimental evidence at protein leveli

Functioni

Involved in virus morphogenesis. Functions as a receptor for the immature double-layered inner capsid particle (ICP) which transiently buds into the lumen of the rough endoplasmic reticulum during viral maturation.4 Publications
Enterotoxin that causes a phospholipase C-dependent elevation of the intracellular calcium concentration in host intestinal mucosa cells. Increased concentration of intracellular calcium disrupts the cytoskeleton and the tight junctions, raising the paracellular permeability. Potentiates chloride ion secretion through a calcium ion-dependent signaling pathway, inducing age-dependent diarrhea. To perform this enterotoxigenic role in vivo, NSP4 is probably released from infected enterocytes in a soluble form capable of diffusing within the intestinal lumen and interacting with the plasma membrane receptors on neighboring epithelial cells. Possible receptors for NSP4 are alpha-1/beta-1 and alpha-2/beta-1 integrin heterodimers.4 Publications

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sitei111 – 1122Cleavage Reviewed prediction
Metal bindingi120 – 1201Calcium; shared with all tetrameric partners; partial
Metal bindingi123 – 1231Calcium; shared with all tetrameric partners

GO - Molecular functioni

  1. metal ion binding Source: UniProtKB-KW

GO - Biological processi

  1. pathogenesis Source: UniProtKB-KW
  2. viral process Source: UniProtKB-KW
Complete GO annotation...

Keywords - Molecular functioni

Enterotoxin, Toxin

Keywords - Biological processi

Host-virus interaction, Virulence

Keywords - Ligandi

Calcium, Metal-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Non-structural glycoprotein 4
Short name:
NSP4
Alternative name(s):
NCVP5
NS28
OrganismiRotavirus A (strain SA11-Both G3-P5B[2]-I2-R2-C5-M5-A5-N2-T5-E2-H5) (RV-A) (Simian Agent 11 (strain Both))
Taxonomic identifieri37137 [NCBI]
Taxonomic lineageiVirusesdsRNA virusesReoviridaeSedoreovirinaeRotavirusRotavirus A
Virus hostiMacaca mulatta (Rhesus macaque) [TaxID: 9544]
ProteomesiUP000007180: Genome

Subcellular locationi

Chain Non-structural glycoprotein 4 : Host rough endoplasmic reticulum membrane; Single-pass type III membrane protein By similarity. Host membranehost caveola; Single-pass type III membrane protein. Secreted By similarity
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. NSP4 also localizes in vesicular structures, which contain an autophagosomal marker and associate with viroplasms in virus-infected cells.6 Publications

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini1 – 2828Lumenal
Add
BLAST
Transmembranei29 – 5123Helical; Reviewed prediction
Add
BLAST
Topological domaini52 – 175124Cytoplasmic
Add
BLAST

GO - Cellular componenti

  1. host caveola Source: UniProtKB-SubCell
  2. host cell rough endoplasmic reticulum membrane Source: UniProtKB-SubCell
  3. integral component of membrane Source: UniProtKB-KW
Complete GO annotation...

Keywords - Cellular componenti

Host endoplasmic reticulum, Host membrane, Membrane, Secreted

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi63 – 631C → S: No effect on receptor activity nor on oligomer formation. No effect on receptor activity nor on oligomer formation; when associated with C-71. 1 Publication
Mutagenesisi71 – 711C → S: No effect on receptor activity nor on oligomer formation. No effect on receptor activity nor on oligomer formation; when associated with C-63. 1 Publication
Mutagenesisi120 – 1201E → A: Complete loss of interaction with integrin ITGA2. 1 Publication
Mutagenesisi166 – 1661Y → I: Loss of ICP-binding activity. 1 Publication
Mutagenesisi174 – 1752Missing: Abolishes receptor activity. 1 Publication
Mutagenesisi175 – 1751M → G, K or I: Abolishes receptor activity. 1 Publication
Mutagenesisi175 – 1751Missing: Abolishes receptor activity. No effect on subcellular location. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 175175Non-structural glycoprotein 4
PRO_0000149628Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Glycosylationi8 – 81N-linked (GlcNAc...) (high mannose); by host1 Publication
Glycosylationi18 – 181N-linked (GlcNAc...) (high mannose); by host1 Publication

Post-translational modificationi

The N-glycosyl content is primarily Man9GlcNAc, with a small amount of Man8GlcNAc.

Keywords - PTMi

Glycoprotein

Interactioni

Subunit structurei

Homotetramer. Forms a complex with the ICP. Interacts, via the active enterotoxic peptide region, with host CAV1, early and late in infection. Interacts with host integrin ITGA1/ITGB1 heterodimer. Interacts with host integrin ITGA2/ITGB1 heterodimer. Interaction with microtubules blocks trafficking to the Golgi apparatus.7 Publications

Protein-protein interaction databases

DIPiDIP-46136N.

Structurei

Secondary structure

Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Helixi96 – 13641

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1G1IX-ray2.00A/B95-137[»]
1G1JX-ray1.86A/B95-137[»]
2O1KX-ray1.67A/B95-146[»]
ProteinModelPortaliP04512.
SMRiP04512. Positions 95-137.

Miscellaneous databases

EvolutionaryTraceiP04512.

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni7 – 2115Hydrophobic By similarity
Add
BLAST
Regioni67 – 8519Hydrophobic By similarity
Add
BLAST
Regioni85 – 12339Endoplasmic reticulum retention signal Reviewed prediction
Add
BLAST
Regioni114 – 13522Interaction with CAV1 By similarity
Add
BLAST
Regioni122 – 17554Required for interaction with microtubules
Add
BLAST
Regioni159 – 17517ICP binding domain
Add
BLAST

Coiled coil

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Coiled coili85 – 11733 Reviewed prediction
Add
BLAST

Domaini

A disordered 28 AA C-terminal domain is presented to the cytoplasm by each subunit of the tetrameric receptor.1 Publication
The coiled coil region mediates oligomerization.1 Publication

Sequence similaritiesi

Belongs to the rotavirus NSP4 family.

Keywords - Domaini

Coiled coil, Signal-anchor, Transmembrane, Transmembrane helix

Family and domain databases

InterProiIPR002107. Rotavirus_NSP4.
[Graphical view]
PfamiPF01452. Rota_NSP4. 1 hit.
[Graphical view]
ProDomiPD002202. NSP4_rotavirus. 1 hit.
[Graphical view] [Entries sharing at least one domain]

Sequencei

Sequence statusi: Complete.

P04512-1 [UniParc]FASTAAdd to Basket

« Hide

MEKLTDLNYT LSVITLMNNT LHTILEDPGM AYFPYIASVL TGLFALNKAS    50
IPTMKIALKT SKCSYKVVKY CIVTIFNTLL KLAGYKEQIT TKDEIEKQMD 100
RVVKEMRRQL EMIDKLTTRE IEQVELLKRI YDKLTVQTTG EIDMTKEINQ 150
KNVRTLEEWE SGKNPYEPRE VTAAM 175
Length:175
Mass (Da):20,267
Last modified:August 13, 1987 - v1
Checksum:i1E72A3223C567309
GO

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
K01138 Genomic RNA. Translation: AAA47291.1.
PIRiA04140. VGXRTS.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
K01138 Genomic RNA. Translation: AAA47291.1 .
PIRi A04140. VGXRTS.

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
Entry Method Resolution (Å) Chain Positions PDBsum
1G1I X-ray 2.00 A/B 95-137 [» ]
1G1J X-ray 1.86 A/B 95-137 [» ]
2O1K X-ray 1.67 A/B 95-146 [» ]
ProteinModelPortali P04512.
SMRi P04512. Positions 95-137.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

DIPi DIP-46136N.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Miscellaneous databases

EvolutionaryTracei P04512.

Family and domain databases

InterProi IPR002107. Rotavirus_NSP4.
[Graphical view ]
Pfami PF01452. Rota_NSP4. 1 hit.
[Graphical view ]
ProDomi PD002202. NSP4_rotavirus. 1 hit.
[Graphical view ] [Entries sharing at least one domain ]
ProtoNeti Search...

Publicationsi

  1. "Coding assignment and nucleotide sequence of simian rotavirus SA11 gene segment 10: location of glycosylation sites suggests that the signal peptide is not cleaved."
    Both G.W., Siegman L.J., Bellamy A.R., Atkinson P.H.
    J. Virol. 48:335-339(1983) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC RNA], SUBCELLULAR LOCATION, CARBOHYDRATE STRUCTURE, GLYCOSYLATION AT ASN-8 AND ASN-18.
  2. "A functional NSP4 enterotoxin peptide secreted from rotavirus-infected cells."
    Zhang M., Zeng C.Q.-Y., Morris A.P., Estes M.K.
    J. Virol. 74:11663-11670(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: PROTEIN SEQUENCE OF 112-120, PROTEOLYTIC CLEAVAGE, FUNCTION.
  3. "Transient expression and mutational analysis of the rotavirus intracellular receptor: the C-terminal methionine residue is essential for ligand binding."
    Taylor J.A., Meyer J.C., Legge M.A., O'Brien J.A., Street J.E., Lord V.J., Bergmann C.C., Bellamy A.R.
    J. Virol. 66:3566-3572(1992) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, SUBUNIT, SUBCELLULAR LOCATION, MUTAGENESIS OF CYS-63; CYS-71; MET-175 AND 174-ALA--MET-175.
  4. "The rotavirus nonstructural glycoprotein NSP4 mobilizes Ca2+ from the endoplasmic reticulum."
    Tian P., Estes M.K., Hu Y., Ball J.M., Zeng C.Q.-Y., Schilling W.P.
    J. Virol. 69:5763-5772(1995) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  5. "The cytoplasmic tail of NSP4, the endoplasmic reticulum-localized non-structural glycoprotein of rotavirus, contains distinct virus binding and coiled coil domains."
    Taylor J.A., O'Brien J.A., Yeager M.
    EMBO J. 15:4469-4476(1996) [PubMed] [Europe PMC] [Abstract]
    Cited for: COILED-COIL DOMAIN.
  6. "The rotavirus enterotoxin NSP4 mobilizes intracellular calcium in human intestinal cells by stimulating phospholipase C-mediated inositol 1,4,5-trisphosphate production."
    Dong Y., Zeng C.Q.-Y., Ball J.M., Estes M.K., Morris A.P.
    Proc. Natl. Acad. Sci. U.S.A. 94:3960-3965(1997) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  7. "Immobilization of the early secretory pathway by a virus glycoprotein that binds to microtubules."
    Xu A., Bellamy A.R., Taylor J.A.
    EMBO J. 19:6465-6474(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH MICROTUBULES, SUBCELLULAR LOCATION.
  8. "Probing the structure of rotavirus NSP4: a short sequence at the extreme C terminus mediates binding to the inner capsid particle."
    O'Brien J.A., Taylor J.A., Bellamy A.R.
    J. Virol. 74:5388-5394(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH ICP, MUTAGENESIS OF TYR-166.
  9. "A cytoplasmic region of the NSP4 enterotoxin of rotavirus is involved in retention in the endoplasmic reticulum."
    Mirazimi A., Magnusson K.-E., Svensson L.
    J. Gen. Virol. 84:875-883(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: ER RETENTION SIGNAL.
  10. "The rotavirus enterotoxin NSP4 directly interacts with the caveolar structural protein caveolin-1."
    Parr R.D., Storey S.M., Mitchell D.M., McIntosh A.L., Zhou M., Mir K.D., Ball J.M.
    J. Virol. 80:2842-2854(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH HUMAN CAV1, SUBCELLULAR LOCATION.
  11. "Rotavirus NSP4 induces a novel vesicular compartment regulated by calcium and associated with viroplasms."
    Berkova Z., Crawford S.E., Trugnan G., Yoshimori T., Morris A.P., Estes M.K.
    J. Virol. 80:6061-6071(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: SUBCELLULAR LOCATION.
  12. "Full-length, glycosylated NSP4 is localized to plasma membrane caveolae by a novel raft isolation technique."
    Storey S.M., Gibbons T.F., Williams C.V., Parr R.D., Schroeder F., Ball J.M.
    J. Virol. 81:5472-5483(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH HUMAN CAV1, SUBCELLULAR LOCATION, GLYCOSYLATION.
    Strain: SA11-4F.
  13. "Inaugural article: integrins alpha1beta1 and alpha2beta1 are receptors for the rotavirus enterotoxin."
    Seo N.-S., Zeng C.Q.-Y., Hyser J.M., Utama B., Crawford S.E., Kim K.J., Hoeoek M., Estes M.K.
    Proc. Natl. Acad. Sci. U.S.A. 105:8811-8818(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH HUMAN INTEGRIN ITGA1/ITGB1 HETERODIMER, INTERACTION WITH HUMAN INTEGRIN ITGA2/ITGB1 HETERODIMER, MUTAGENESIS OF GLU-120.
  14. "Crystal structure of the oligomerization domain of NSP4 from rotavirus reveals a core metal-binding site."
    Bowman G.D., Nodelman I.M., Levy O., Lin S.L., Tian P., Zamb T.J., Udem S.A., Venkataraghavan B., Schutt C.E.
    J. Mol. Biol. 304:861-871(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (1.86 ANGSTROMS) OF 95-137 IN COMPLEX WITH CALCIUM OR STRONTIUM, METAL-BINDING AT GLN-123 AND GLU-120, SUBUNIT.

Entry informationi

Entry nameiNSP4_ROTS1
AccessioniPrimary (citable) accession number: P04512
Entry historyi
Integrated into UniProtKB/Swiss-Prot: August 13, 1987
Last sequence update: August 13, 1987
Last modified: February 19, 2014
This is version 83 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programViral Protein Annotation Program

Miscellaneousi

Miscellaneous

Binds 1 calcium ion per tetramer. The calcium ion is bound by a glutamine from each tetrameric partner and by a glutamic acid from two of the tetrameric partners, while the glutamic acid from the other two partners do not participate in binding the ion By similarity.

Caution

A candidate enterotoxigenic cleaved form of the protein has been suggested [1 Publication], but it remains unclear whether this truncated form constitutes an active enterotoxin in vivo.

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing

Documents

  1. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  2. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

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