1g1i

Structural highlights

Function

NSP4_ROTS1 Plays an essential role in the virus replication cycle by acting as a viroporin. Creates a pore in the host reticulum endoplasmic and as a consequence releases Ca(2+) in the cytoplasm of infected cell. In turn, high levels of cytoplasmic calcium trigger membrane trafficking and transport of viral ER-associated proteins to viroplasms, sites of viral genome replication and immature particle assembly.[HAMAP-Rule:MF_04091]^{[1] [2] [3]} The secreted form acts as an enterotoxin that causes 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 released from infected enterocytes in a soluble form capable of diffusing within the intestinal lumen and interacting with host plasma membrane receptors on neighboring epithelial cells such as integrins ITGA1/ITGB1 and ITGA2/ITGB1.[HAMAP-Rule:MF_04091]^{[4] [5]}

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

References

1. ↑ Hyser JM, Collinson-Pautz MR, Utama B, Estes MK. Rotavirus disrupts calcium homeostasis by NSP4 viroporin activity. mBio. 2010 Nov 30;1(5):e00265-10. PMID:21151776 doi:10.1128/mBio.00265-10
2. ↑ Tian P, Estes MK, Hu Y, Ball JM, Zeng CQ, Schilling WP. The rotavirus nonstructural glycoprotein NSP4 mobilizes Ca2+ from the endoplasmic reticulum. J Virol. 1995 Sep;69(9):5763-72. PMID:7637021 doi:10.1128/JVI.69.9.5763-5772.1995
3. ↑ Dong Y, Zeng CQ, Ball JM, Estes MK, Morris AP. The rotavirus enterotoxin NSP4 mobilizes intracellular calcium in human intestinal cells by stimulating phospholipase C-mediated inositol 1,4,5-trisphosphate production. Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3960-5. PMID:9108087 doi:10.1073/pnas.94.8.3960
4. ↑ Bugarcic A, Taylor JA. Rotavirus nonstructural glycoprotein NSP4 is secreted from the apical surfaces of polarized epithelial cells. J Virol. 2006 Dec;80(24):12343-9. PMID:17035333 doi:10.1128/JVI.01378-06
5. ↑ Seo NS, Zeng CQ, Hyser JM, Utama B, Crawford SE, Kim KJ, Höök M, Estes MK. Integrins alpha1beta1 and alpha2beta1 are receptors for the rotavirus enterotoxin. Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):8811-8. PMID:18587047 doi:10.1073/pnas.0803934105
6. ↑ Bowman GD, Nodelman IM, Levy O, Lin SL, Tian P, Zamb TJ, Udem SA, Venkataraghavan B, Schutt CE. Crystal structure of the oligomerization domain of NSP4 from rotavirus reveals a core metal-binding site. J Mol Biol. 2000 Dec 15;304(5):861-71. PMID:11124032 doi:10.1006/jmbi.2000.4250