| Structural highlights
Function
AP3A_SARS Forms homotetrameric potassium sensitive ion channels (viroporin) and may modulate virus release. Up-regulates expression of fibrinogen subunits FGA, FGB and FGG in host lung epithelial cells. Induces apoptosis in cell culture. Down-regulates the type 1 interferon receptor by inducing serine phosphorylation within the IFN alpha-receptor subunit 1 (IFNAR1) degradation motif and increasing IFNAR1 ubiquitination.[1] [2] [3] [4]
Publication Abstract from PubMed
The severe acute respiratory syndrome associated coronavirus 2 (SARS-CoV-2) and SARS-CoV-1 accessory protein Orf3a colocalizes with markers of the plasma membrane, endocytic pathway, and Golgi apparatus. Some reports have led to annotation of both Orf3a proteins as viroporins. Here we show that neither SARS-CoV-2 nor SARS-CoV-1 Orf3a form functional ion conducting pores and that the conductances measured are common contaminants in overexpression and with high levels of protein in reconstitution studies. Cryo-EM structures of both SARS-CoV-2 and SARS-CoV-1 Orf3a display a narrow constriction and the presence of a positively-charged aqueous vestibule, which would not favor cation permeation. We observe enrichment of the late endosomal marker Rab7 upon SARS-CoV-2 Orf3a overexpression, and co-immunoprecipitation with VPS39. Interestingly, SARS-CoV-1 Orf3a does not cause the same cellular phenotype as SARS-CoV-2 Orf3a and does not interact with VPS39. To explain this difference, we find that a divergent, unstructured loop of SARS-CoV-2 Orf3a facilitates its binding with VPS39, a HOPS complex tethering protein involved in late endosome and autophagosome fusion with lysosomes. We suggest that the added loop enhances SARS-CoV-2 Orf3a's ability to co-opt host cellular trafficking mechanisms for viral exit or host immune evasion.
The SARS-CoV-2 accessory protein Orf3a is not an ion channel, but does interact with trafficking proteins.,Miller AN, Houlihan PR, Matamala E, Cabezas-Bratesco D, Lee GY, Cristofori-Armstrong B, Dilan TL, Sanchez-Martinez S, Matthies D, Yan R, Yu Z, Ren D, Brauchi SE, Clapham DE Elife. 2023 Jan 25;12:e84477. doi: 10.7554/eLife.84477. PMID:36695574[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Law PTW, Wong CH, Au TCC, Chuck CP, Kong SK, Chan PKS, To KF, Lo AWI, Chan JYW, Suen YK, Chan HYE, Fung KP, Waye MMY, Sung JJY, Lo YMD, Tsui SKW. The 3a protein of severe acute respiratory syndrome-associated coronavirus induces apoptosis in Vero E6 cells. J Gen Virol. 2005 Jul;86(Pt 7):1921-1930. PMID:15958670 doi:10.1099/vir.0.80813-0
- ↑ Tan YJ, Tham PY, Chan DZ, Chou CF, Shen S, Fielding BC, Tan TH, Lim SG, Hong W. The severe acute respiratory syndrome coronavirus 3a protein up-regulates expression of fibrinogen in lung epithelial cells. J Virol. 2005 Aug;79(15):10083-7. PMID:16014971 doi:10.1128/JVI.79.15.10083-10087.2005
- ↑ Lu W, Zheng BJ, Xu K, Schwarz W, Du L, Wong CK, Chen J, Duan S, Deubel V, Sun B. Severe acute respiratory syndrome-associated coronavirus 3a protein forms an ion channel and modulates virus release. Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12540-5. PMID:16894145 doi:10.1073/pnas.0605402103
- ↑ Minakshi R, Padhan K, Rani M, Khan N, Ahmad F, Jameel S. The SARS Coronavirus 3a protein causes endoplasmic reticulum stress and induces ligand-independent downregulation of the type 1 interferon receptor. PLoS One. 2009 Dec 17;4(12):e8342. PMID:20020050 doi:10.1371/journal.pone.0008342
- ↑ Miller AN, Houlihan PR, Matamala E, Cabezas-Bratesco D, Lee GY, Cristofori-Armstrong B, Dilan TL, Sanchez-Martinez S, Matthies D, Yan R, Yu Z, Ren D, Brauchi SE, Clapham DE. The SARS-CoV-2 accessory protein Orf3a is not an ion channel, but does interact with trafficking proteins. Elife. 2023 Jan 25;12:e84477. PMID:36695574 doi:10.7554/eLife.84477
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