Login Register Cart 0
Generic placeholder image

Protein & Peptide Letters

Editor-in-Chief

ISSN (Print): 0929-8665
ISSN (Online): 1875-5305

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Computational Analysis of Domains Vulnerable to HPV-16 E6 Oncoprotein and Corresponding Hot Spot Residues

Author(s): Rabbiah Manzoor Malik*, Sahar Fazal and Mohammad Amjad Kamal

Volume 28, Issue 4, 2021

Published on: 22 July, 2020

Page: [414 - 425] Pages: 12

DOI: 10.2174/0929866527666200722134801

Price: $65

Abstract

Background: Human Papilloma Virus (HPV) is the primary cause of cancers in cervix, head and neck regions. Oncoprotein E6 of HPV-16, after infecting human body, alters host protein- protein interaction networks. E6 interacts with several proteins, causing the infection to progress into cervical cancer. The molecular basis for these interactions is the presence of short linear peptide motifs on E6 identical to those on human proteins.

Methods: Motifs of LXXLL and E/DLLL/V-G after identification on E6, were analyzed for their dynamic fluctuations by use of elastic network models. Correlation analysis of amino acid residues of E6 was also performed in specific regions of motifs.

Results: Arginine, Leucine, Glutamine, Threonine and Glutamic acid have been identified as hot spot residues of E6 which can subsequently provide a platform for drug designing and understanding of pathogenesis of cervical cancer. These amino acids play a significant role in stabilizing interactions with host proteins, ultimately causing infections and cancers.

Conclusion: Our study validates the role of linear binding motifs of E6 of HPV in interacting with these proteins as an important event in the propagation of HPV in human cells and its transformation into cervical cancer. The study further predicts the domains of protein kinase and armadillo as part of the regions involved in the interaction of E6AP, Paxillin and TNF R1, with viral E6.

Keywords: E6, hPV, cervical cancer, protein interactions, motifs, domains, e6AP, paxillin, tNF R1, elastic network models.

« Previous Next »
Graphical Abstract

[1]
Goodacre, N.; Devkota, P.; Bae, E.; Wuchty, S.; Uetz, P. Protein-protein interactions of human viruses. Semin. Cell Dev. Biol., 2018, 17
[http://dx.doi.org/10.1016/j.semcdb.2018.07.018] [PMID: 30031213]
[2]
Guven-Maiorov, E.; Tsai, C.J.; Nussinov, R. Structural host-microbiota interaction networks. PLoS Comput. Biol., 2017, 13(10), e1005579.
[http://dx.doi.org/10.1371/journal.pcbi.1005579] [PMID: 29023448]
[3]
Kurkcuoglu, O.; Kurkcuoglu, Z.; Doruker, P.; Jernigan, R.L. Collective dynamics of the ribosomal tunnel revealed by elastic network modeling. Proteins, 2009, 75(4), 837-845.
[http://dx.doi.org/10.1002/prot.22292] [PMID: 19004020]
[4]
Bauer, J.A.; Pavlović, J.; Bauerová-Hlinková, V. Normal mode analysis as a routine part of a structural investigation. Molecules, 2019, 24(18), 3293.
[http://dx.doi.org/10.3390/molecules24183293] [PMID: 31510014]
[5]
Kmiecik, S.; Kouza, M.; Badaczewska-Dawid, A.E.; Kloczkowski, A.; Kolinski, A. Modeling of protein structural flexibility and large-scale dynamics: coarse-grained simulations and elastic network models. Int. J. Mol. Sci., 2018, 19(11), 3496.
[http://dx.doi.org/10.3390/ijms19113496] [PMID: 30404229]
[6]
Hu, G.; Paola, L.D.; Liang, Z.; Giuliani, A. Comparative study of elastic network model and protein contact network for protein complexes: the hemoglobin case. BioMed. Res. Int., 2017, 15, 2483264.
[7]
Kranjec, C.; Tomaić, V.; Massimi, P.; Nicolaides, L.; Doorbar, J.; Banks, L. The high-risk HPV E6 target scribble (hScrib) is required for HPV E6 expression in cervical tumour-derived cell lines. Papillomavirus Res., 2016, 2, 70-77.
[http://dx.doi.org/10.1016/j.pvr.2016.04.001] [PMID: 29074188]
[8]
Ganti, K.; Massimi, P.; Manzo-Merino, J.; Tomaić, V.; Pim, D.; Playford, M.P.; Lizano, M.; Roberts, S.; Kranjec, C.; Doorbar, J.; Banks, L. Interaction of the Human papillomavirus E6 oncoprotein with sorting nexin 27 modulates endocytic cargo transport pathways. PLoS Pathog., 2016, 12(9), e1005854.
[http://dx.doi.org/10.1371/journal.ppat.1005854] [PMID: 27649450]
[9]
Squarzanti, D.F.; Sorrentino, R.; Landini, M.M.; Chiesa, A.; Pinato, S.; Rocchio, F.; Mattii, M.; Penengo, L.; Azzimonti, B. Human papillomavirus type 16 E6 and E7 oncoproteins interact with the nuclear p53-binding protein 1 in an in vitro reconstructed 3D epithelium: new insights for the virus-induced DNA damage response. Virol. J., 2018, 15(1), 176.
[http://dx.doi.org/10.1186/s12985-018-1086-4] [PMID: 30445982]
[10]
Moreira, I.S.; Koukos, P.I.; Melo, R.; Almeida, J.G.; Preto, A.J.; Schaarschmidt, J.; Trellet, M.; Gümüş, Z.H.; Costa, J.; Bonvin, A.M.J.J. SpotOn: high accuracy identification of protein-protein interface hot-spots. Sci. Rep., 2017, 7(1), 8007.
[http://dx.doi.org/10.1038/s41598-017-08321-2] [PMID: 28808256]
[11]
Dinkel, H.; Van Roey, K.; Michael, S.; Kumar, M.; Uyar, B.; Altenberg, B.; Milchevskaya, V.; Schneider, M.; Kühn, H.; Behrendt, A.; Dahl, S.L.; Damerell, V.; Diebel, S.; Kalman, S.; Klein, S.; Knudsen, A.C.; Mäder, C.; Merrill, S.; Staudt, A.; Thiel, V.; Welti, L.; Davey, N.E.; Diella, F.; Gibson, T.J. ELM 2016--data update and new functionality of the eukaryotic linear motif resource. Nucleic Acids Res., 2016, 44(D1), D294-D300.
[http://dx.doi.org/10.1093/nar/gkv1291] [PMID: 26615199]
[12]
Pundir, S.; Martin, M.J.; O’Donovan, C. UniProt protein knowledgebase. Methods Mol. Biol., 2017, 1558, 41-55.
[http://dx.doi.org/10.1007/978-1-4939-6783-4_2] [PMID: 28150232]
[13]
Ma, J.; Wang, S.; Zhao, F.; Xu, J. Protein threading using context-specific alignment potential. Bioinformatics (Proceedings of ISMB 2013), 2013, 129(13), 257-265.
[14]
Eyal, E.; Lum, G.; Bahar, I. The anisotropic network model web server at 2015 (ANM 2.0). Bioinformatics, 2015, 31(9), 1487-1489.
[http://dx.doi.org/10.1093/bioinformatics/btu847] [PMID: 25568280]
[15]
Källberg, M.; Wang, H.; Wang, S.; Peng, J.; Wang, Z.; Lu, H.; Xu, J. Template-based protein structure modeling using the RaptorX web server. Nat. Protoc., 2012, 7(8), 1511-1522.
[http://dx.doi.org/10.1038/nprot.2012.085] [PMID: 22814390]
[16]
Songyang, Z.; Fanning, A.S.; Fu, C.; Xu, J.; Marfatia, S.M.; Chishti, A.H.; Crompton, A.; Chan, A.C.; Anderson, J.M.; Cantley, L.C. Recognition of unique carboxyl-terminal motifs by distinct PDZ domains. Science, 1997, 275(5296), 73-77.
[http://dx.doi.org/10.1126/science.275.5296.73] [PMID: 8974395]
[17]
Atilgan, A.R.; Durell, S.R.; Jernigan, R.L.; Demirel, M.C.; Keskin, O.; Bahar, I. Anisotropy of fluctuation dynamics of proteins with an elastic network model. Biophys. J., 2001, 80(1), 505-515.
[http://dx.doi.org/10.1016/S0006-3495(01)76033-X] [PMID: 11159421]
[18]
Pim, D.; Bergant, M.; Boon, S.S.; Ganti, K.; Kranjec, C.; Massimi, P.; Subbaiah, V.K.; Thomas, M.; Tomaić, V.; Banks, L. Human papillomaviruses and the specificity of PDZ domain targeting. FEBS J., 2012, 279(19), 3530-3537.
[http://dx.doi.org/10.1111/j.1742-4658.2012.08709.x] [PMID: 22805590]
[19]
Martinez-Zapien, D.; Ruiz, F.X.; Poirson, J.; Mitschler, A.; Ramirez, J.; Forster, A.; Cousido-Siah, A.; Masson, M.; Vande Pol, S.; Podjarny, A.; Travé, G.; Zanier, K. Structure of the E6/E6AP/p53 complex required for HPV-mediated degradation of p53. Nature, 2016, 529(7587), 541-545.
[http://dx.doi.org/10.1038/nature16481] [PMID: 26789255]
[20]
Tomaić V. Functional roles of E6 and E7 oncoproteins in HPV-induced malignancies at diverse anatomical sites. Cancers (Basel), 2016, (10), 95.
[21]
Chen, S.C.; Bahar, I. Mining frequent patterns in protein structures: a study of protease families. Bioinformatics, 2004, 20(Suppl. 1), i77-i85.
[http://dx.doi.org/10.1093/bioinformatics/bth912] [PMID: 15262784]
[22]
Sen, T.Z.; Feng, Y.; Garcia, J.V.; Kloczkowski, A.; Jernigan, R.L. The extent of cooperativity of protein motions observed with elastic network models is similar for atomic and coarser-grained models. J. Chem. Theory Comput., 2006, 2(3), 696-704.
[http://dx.doi.org/10.1021/ct600060d] [PMID: 17710199]
[23]
Javier, R.T. Cell polarity proteins: common targets for tumorigenic human viruses. Oncogene, 2008, 27(55), 7031-7046.
[http://dx.doi.org/10.1038/onc.2008.352] [PMID: 19029943]
[24]
van Ham, M.; Hendriks, W. PDZ domains-glue and guide. Mol. Biol. Rep., 2003, 30(2), 69-82.
[http://dx.doi.org/10.1023/A:1023941703493] [PMID: 12841577]
[25]
Genera, M.; Samson, D.; Raynal, B.; Haouz, A.; Baron, B.; Simenel, C.; Guerois, R.; Wolff, N.; Caillet-Saguy, C. Structural and functional characterization of the PDZ domain of the human phosphatase PTPN3 and its interaction with the human papillomavirus E6 oncoprotein. Sci. Rep., 2019, 9(1), 7438.
[http://dx.doi.org/10.1038/s41598-019-43932-x] [PMID: 31092861]
[26]
Boon, S.S.; Tomaić, V.; Thomas, M.; Roberts, S.; Banks, L. Cancer-causing human papillomavirus E6 proteins display major differences in the phospho-regulation of their PDZ interactions. J. Virol., 2015, 89(3), 1579-1586.
[http://dx.doi.org/10.1128/JVI.01961-14] [PMID: 25410862]
[27]
Zhan, L.; Rosenberg, A.; Bergami, K.C.; Yu, M.; Xuan, Z.; Jaffe, A.B.; Allred, C.; Muthuswamy, S.K. Deregulation of scribble promotes mammary tumorigenesis and reveals a role for cell polarity in carcinoma. Cell, 2008, 135(5), 865-878.
[http://dx.doi.org/10.1016/j.cell.2008.09.045] [PMID: 19041750]
[28]
Liu, Y.; Henry, G.D.; Hegde, R.S.; Baleja, J.D. Solution structure of the hDlg/SAP97 PDZ2 domain and its mechanism of interaction with HPV-18 papillomavirus E6 protein. Biochemistry, 2007, 46(38), 10864-10874.
[http://dx.doi.org/10.1021/bi700879k] [PMID: 17713926]
[29]
Zhang, Y.; Dasgupta, J.; Ma, R.Z.; Banks, L.; Thomas, M.; Chen, X.S. Structures of a human papillomavirus (HPV) E6 polypeptide bound to MAGUK proteins: mechanisms of targeting tumor suppressors by a high-risk HPV oncoprotein. J. Virol., 2007, 81(7), 3618-3626.
[http://dx.doi.org/10.1128/JVI.02044-06] [PMID: 17267502]
[30]
Tomaić, V.; Gardiol, D.; Massimi, P.; Ozbun, M.; Myers, M.; Banks, L. Human and primate tumour viruses use PDZ binding as an evolutionarily conserved mechanism of targeting cell polarity regulators. Oncogene, 2009, 28(1), 1-8.
[http://dx.doi.org/10.1038/onc.2008.365] [PMID: 18820705]
[31]
Patel, D.; Huang, S.M.; Baglia, L.A.; McCance, D.J. The E6 protein of human papillomavirus type 16 binds to and inhibits co-activation by CBP and p300. EMBO J., 1999, 18(18), 5061-5072.
[http://dx.doi.org/10.1093/emboj/18.18.5061] [PMID: 10487758]
[32]
Filippova, M.; Johnson, M.M.; Bautista, M.; Filippov, V.; Fodor, N.; Tungteakkhun, S.S.; Williams, K.; Duerksen-Hughes, P.J. The large and small isoforms of human papillomavirus type 16 E6 bind to and differentially affect procaspase 8 stability and activity. J. Virol., 2007, 81(8), 4116-4129.
[http://dx.doi.org/10.1128/JVI.01924-06] [PMID: 17267478]
[33]
Degenhardt, Y.Y.; Silverstein, S.J. Gps2, a protein partner for human papillomavirus E6 proteins. J. Virol., 2001, 75(1), 151-160.
[http://dx.doi.org/10.1128/JVI.75.1.151-160.2001] [PMID: 11119584]
[34]
Filippova, M.; Parkhurst, L.; Duerksen-Hughes, P.J. The human papillomavirus 16 E6 protein binds to Fas-associated death domain and protects cells from Fas-triggered apoptosis. J. Biol. Chem., 2004, 279(24), 25729-25744.
[http://dx.doi.org/10.1074/jbc.M401172200] [PMID: 15073179]
[35]
Kumar, A.; Zhao, Y.; Meng, G.; Zeng, M.; Srinivasan, S.; Delmolino, L.M.; Gao, Q.; Dimri, G.; Weber, G.F.; Wazer, D.E.; Band, H.; Band, V. Human papillomavirus oncoprotein E6 inactivates the transcriptional coactivator human ADA3. Mol. Cell. Biol., 2002, 22(16), 5801-5812.
[http://dx.doi.org/10.1128/MCB.22.16.5801-5812.2002] [PMID: 12138191]
[36]
Gewin, L.; Myers, H.; Kiyono, T.; Galloway, D.A. Identification of a novel telomerase repressor that interacts with the human papillomavirus type-16 E6/E6-AP complex. Genes Dev., 2004, 18(18), 2269-2282.
[http://dx.doi.org/10.1101/gad.1214704] [PMID: 15371341]
[37]
Thomas, M.; Banks, L. Human papillomavirus (HPV) E6 interactions with Bak are conserved amongst E6 proteins from high and low risk HPV types. J. Gen. Virol., 1999, 80(Pt 6), 1513-1517.
[http://dx.doi.org/10.1099/0022-1317-80-6-1513] [PMID: 10374970]
[38]
Zimmermann, H.; Degenkolbe, R.; Bernard, H.U.; O’Connor, M.J. The human papillomavirus type 16 E6 oncoprotein can down-regulate p53 activity by targeting the transcriptional coactivator CBP/p300. J. Virol., 1999, 73(8), 6209-6219.
[http://dx.doi.org/10.1128/JVI.73.8.6209-6219.1999] [PMID: 10400710]
[39]
Howie, H.L.; Katzenellenbogen, R.A.; Galloway, D.A. Papillomavirus E6 proteins. J. Viorol., 2009, 384(2), 324-334.
[http://dx.doi.org/10.1016/j.virol.2008.11.017]
[40]
Filippova, M.; Song, H.; Connolly, J.L.; Dermody, T.S.; Duerksen-Hughes, P.J. The human papillomavirus 16 E6 protein binds to tumor necrosis factor (TNF) R1 and protects cells from TNF-induced apoptosis. J. Biol. Chem., 2002, 277(24), 21730-21739.
[http://dx.doi.org/10.1074/jbc.M200113200] [PMID: 11934887]
[41]
Oppermann, F.S.; Gnad, F.; Olsen, J.V.; Hornberger, R.; Greff, Z.; Kéri, G.; Mann, M.; Daub, H. Large-scale proteomics analysis of the human kinome. Mol. Cell. Proteomics, 2009, 8(7), 1751-1764.
[http://dx.doi.org/10.1074/mcp.M800588-MCP200] [PMID: 19369195]
[42]
Lampert, F.; Stafa, D.; Goga, A.; Soste, M.V.; Gilberto, S.; Olieric, N.; Picotti, P.; Stoffel, M.; Peter, M. The multi-subunit GID/CTLH E3 ubiquitin ligase promotes cell proliferation and targets the transcription factor Hbp1 for degradation. eLife, 2018, 7, 7.
[http://dx.doi.org/10.7554/eLife.35528] [PMID: 29911972]

Rights & Permissions Print Cite
Article Metrics
9
1
© 2024 Bentham Science Publishers | Privacy Policy