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1.C.99 The Pore-forming Corona Viral Orf8a (Sars8a) Family

The mechanisms and functions of viral channel proteins have been reviewed by Fischer and Hsu (2011) and Fischer et al. (2012). ORF8a protein is 39 residues long and contains a single transmembrane domain. The protein has been synthesized using solid phase peptide synthesis and reconstituted into artificial lipid bilayers (Chen et al., 2011). It forms cation-selective ion channels with a main conductance level of 8.9±0.8pS at elevated temperature (38.5°C). Computational modeling studies including multi nanosecond molecular dynamics simulations in a hydrated POPC lipid bilayer are done with a 22 amino acid transmembrane helix to predict a putative homooligomeric helical bundle model. A structural model of a pentameric bundle was proposed by Chen et al. (2011) with cysteines, serines and threonines facing the pore. The following Corina viral proteins have been considered to be viroporins, The (1) E protein, (2) ORF7b (TC# 1.A.127), (3) ORF10 (TC# 1.A.128), (4) Orf3a (TC# 1.A.57) and (5) ORF8a (TC# 1.C.99), but some researchers have questioned some of these conclusions (Harrison et al. 2022).

As noted above, permeability results from the assembly of helical bundles. Computational models of a pentameric assembly of 8a peptides were generated using the first 22 amino acids which include the single TMS. Low energy structures reveal a hydrophilic pore mantled by residues Thr-8, and -18, Ser-11, Cys-13, and Arg-22. Potential of mean force profiles for Na+ , K+ , Cl- and Ca2+ along the pore were calculated, leading to prediction of weak cation selectivity in agreement with the experimental results (Hsu et al. 2015). 3-D structures of short homologues are available (1XAK_A of 83 aas and 1 TMS, and 1Y04_A of 87 aas and 1 TMS). Members of subfamilies 1.C.99.1 and 1.C.99.2 are similar in their first 38 aas which encompasses the first (N-terminal) TMS.

References associated with 1.C.99 family:

Barrantes, F.J. (2021). Structural biology of coronavirus ion channels. Acta Crystallogr D Struct Biol 77: 391-402. 33825700
Chen, C.C., J. Krüger, I. Sramala, H.J. Hsu, P. Henklein, Y.M. Chen, and W.B. Fischer. (2011). ORF8a of SARS-CoV forms an ion channel: experiments and molecular dynamics simulations. Biochim. Biophys. Acta. 1808: 572-579. 20708597
Fischer, W.B. and H.J. Hsu. (2011). Viral channel forming proteins - modeling the target. Biochim. Biophys. Acta. 1808: 561-571. 20546700
Fischer, W.B., Y.T. Wang, C. Schindler, and C.P. Chen. (2012). Mechanism of function of viral channel proteins and implications for drug development. Int Rev Cell Mol Biol 294: 259-321. 22364876
Harrison, N.L., G.W. Abbott, M. Gentzsch, A. Aleksandrov, A. Moroni, G. Thiel, S. Grant, C.G. Nichols, H.A. Lester, A. Hartel, K. Shepard, D.C. Garcia, and M. Yazawa. (2022). How many SARS-CoV-2 "viroporins" are really ion channels? Commun Biol 5: 859. 36008538
Hsu, H.J., M.H. Lin, C. Schindler, and W.B. Fischer. (2015). Structure based computational assessment of channel properties of assembled ORF-8a from SARS-CoV. Proteins 83: 300-308. 25394339
Mann, M.M., M.K. Hsieh, J.D. Tang, W.S. Hart, M.J. Lazzara, J.B. Klauda, and B.W. Berger. (2023). Understanding how transmembrane domains regulate interactions between human BST-2 and the SARS-CoV-2 accessory protein ORF7a. Biochim. Biophys. Acta. Biomembr 1865: 184174. [Epub: Ahead of Print] 37211321
Martin, S., G. Jégou, A. Nicolas, M. Le Gallo, &.#.2.0.1.;. Chevet, F. Godey, and T. Avril. (2022). A cell-based system combined with flow cytometry to evaluate antibody responses against SARS-CoV-2 transmembrane proteins in patients with COVID-19. STAR Protoc 3: 101229. 35287269
Scott, C. and S. Griffin. (2015). Viroporins: structure, function and potential as antiviral targets. J Gen Virol 96: 2000-2027. 26023149