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http://dx.doi.org/10.5483/BMBRep.2016.49.8.021

Structural investigation on the intrinsically disordered N-terminal region of HPV16 E7 protein  

Lee, Chewook (Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology)
Kim, Do-Hyoung (Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology)
Lee, Si-Hyung (Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology)
Su, Jiulong (Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology)
Han, Kyou-Hoon (Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology)
Publication Information
BMB Reports / v.49, no.8, 2016 , pp. 431-436 More about this Journal
Abstract
Human papillomavirus (HPV) is the major cause of cervical cancer, a deadly threat to millions of females. The early oncogene product (E7) of the high-risk HPV16 is the primary agent associated with HPV-related cervical cancers. In order to understand how E7 contributes to the transforming activity, we investigated the structural features of the flexible N-terminal region (46 residues) of E7 by carrying out N-15 heteronuclear NMR experiments and replica exchange molecular dynamics simulations. Several NMR parameters as well as simulation ensemble structures indicate that this intrinsically disordered region of E7 contains two transient (10-20% populated) helical pre-structured motifs that overlap with important target binding moieties such as an E2F-mimic motif and a pRb-binding LXCXE segment. Presence of such target-binding motifs in HPV16 E7 provides a reasonable explanation for its promiscuous target-binding behavior associated with its transforming activity.
Keywords
E7 oncoprotein; Human papillomavirus (HPV); Intrinsically disordered protein (IDP); Molecular dynamics (MD) simulation; Nuclear magnetic resonance (NMR); Pre-structured motif (PreSMo);
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1 Frazer I (2002) Vaccines for papillomavirus infection. Virus Res 89, 271-274   DOI
2 Roman A and Munger K (2013) The papillomavirus E7 proteins. Virology 445, 138-168   DOI
3 McLaughlin-Drubin ME, Meyers J and Munger K (2012) Cancer associated human papillomaviruses. Curr Opin Virol 2, 459-466   DOI
4 Chemes LB, Glavina J, Faivovich J, de Prat-Gay G and Sanchez IE (2012) Evolution of linear motifs within the papillomavirus E7 oncoprotein. J Mol Biol 422, 336-346   DOI
5 Munger K, Basile JR, Duensing S et al (2001) Biological activities and molecular targets of the human papillomavirus E7 oncoprotein. Oncogene 20, 7888-7898   DOI
6 Lee SH, Cha EJ, Lim JE et al (2012) Structural characterization of an intrinsically unfolded mini-HBX protein from hepatitis B virus. Mol Cells 34, 165-169   DOI
7 Garcia-Alai MM, Alonso LG and de Prat-Gay G (2007) The N-terminal module of HPV16 E7 is an intrinsically disordered domain that confers conformational and recognition plasticity to the oncoprotein. Biochemistry 46, 10405-10412   DOI
8 Liu X, Clements A, Zhao K and Marmorstein R (2005) Structure of the human papillomavirus E7 oncoprotein and its mechanism for inactivation of the retinoblastoma tumor suppressor. J Biol Chem 281, 578-586   DOI
9 Ohlenschlager O, Seiboth T, Zengerling H et al (2006) Solution structure of the partially folded high-risk human papilloma virus 45 oncoprotein E7. Oncogene 25, 5953-5959   DOI
10 Todorovic B, Massimi P, Hung K, Shaw GS, Banks L and Mymryk JS (2011) Systematic analysis of the amino acid residues of human papillomavirus type 16 E7 conserved region 3 involved in dimerization and transformation. J Virol 85, 10048-10057   DOI
11 Alonso LG, García-Alai MM, Nadra AD et al (2002) High-risk (HPV16) human papillomavirus E7 oncoprotein is highly stable and extended, with conformational transitions that could explain its multiple cellular binding partners. Biochemistry 41, 10510-10518   DOI
12 Clements A, Johnston K, Mazzarelli JM, Ricciardi RP and Marmorstein R (2000) Oligomerization properties of the viral oncoproteins adenovirus E1A and human papillomavirus E7 and their complexes with the retinoblastoma protein. Biochemistry 39, 16033-16045   DOI
13 Alonso LG, García-Alai MM, Smal C et al (2004) The HPV16 E7 viral oncoprotein self-assembles into defined spherical oligomers. Biochemistry 43, 3310-3317   DOI
14 Dunker AK, Babu MM, Barbar E et al (2013) What’s in a name? Why these proteins are intrinsically disordered. Intrinsically Disordered Proteins 1, e24157   DOI
15 Lee S-H, Kim D-H, Han JJ et al (2012) Understanding pre-structured motifs (PreSMos) in intrinsically unfolded proteins. Curr Protein Pept Sci 13, 34-54   DOI
16 Uversky VN, Oldfield CJ and Dunker AK (2008) Intrinsically disordered proteins in human diseases: Introducing the D2 concept. Ann Rev Biophys 37, 215-246   DOI
17 Fletcher CM and Wagner G (1998) The interaction of eIF4E with 4E-BP1 is an induced fit to a completely disordered protein. Protein Sci 7, 1639-1642   DOI
18 James TL, Liu H, Ulyanov NB et al (1997) Solution structure of a 142-residue recombinant prion protein corresponding to the infectious fragment of the scrapie isoform. Proc Natl Acad Sci U S A 94, 10086-10091   DOI
19 Xue B, Blocquel D, Habchi J et al (2014) Structural disorder in viral proteins. Chem Rev 114, 6880-6911   DOI
20 Radhakrishnan I, Pérez-Alvarado GC, Parker D, Dyson HJ, Montminy MR and Wright PE (1997) Solution structure of the KIX domain of CBP bound to the transactivation domain of CREB: A model for activator:coactivator interactions. Cell 91, 741-752   DOI
21 De Guzman RN, Wojciak JM, Martinez-Yamout MA, Dyson HJ and Wright PE (2005) CBP/p300 TAZ1 domain forms a structured scaffold for ligand binding. Biochemistry 44, 490-497   DOI
22 Di Lello P, Jenkins LMM, Jones TN et al (2006) Structure of the Tfb1/p53 complex: Insights into the interaction between the p62/Tfb1 subunit of TFIIH and the activation domain of p53. Mol Cell 22, 731-740   DOI
23 Rowell JP, Simpson KL, Stott K, Watson M and Thomas JO (2012) HMGB1-facilitated p53 DNA binding occurs via HMG-Box/p53 transactivation domain interaction, regulated by the acidic tail. Structure 20, 2014-2024   DOI
24 Ha J-H, Shin J-S, Yoon M-K et al (2013) Dual-site interactions of p53 protein transactivation domain with anti-apoptotic Bcl-2 family proteins reveal a highly convergent mechanism of divergent p53 pathways. J Biol Chem 288, 7387-7398   DOI
25 Chi S-W, Lee S-H, Kim D-H et al (2005) Structural details on mdm2-p53 interaction. J Biol Chem 280, 38795-38802   DOI
26 Lee CW, Martinez-Yamout MA, Dyson HJ and Wright PE (2010) Structure of the p53 transactivation domain in complex with the nuclear coactivator binding domain of CBP. Biochemistry 49, 9964-9971   DOI
27 Bochkareva E, Kaustov L, Ayed A et al (2005) Single-stranded DNA mimicry in the p53 transactivation domain interaction with replication protein A. Proc Natl Acad Sci U S A 102, 15412-15417   DOI
28 Lee H, Mok KH, Muhandiram R et al (2000) Local structural elements in the mostly unstructured transcriptional activation domain of human p53. J Biol Chem 275, 29426-29432   DOI
29 Noval MG, Gallo M, Perrone S, Salvay AG, Chemes LB and de Prat-Gay G (2013) Conformational dissection of a viral intrinsically disordered domain involved in cellular transformation. PLoS One 8, e72760   DOI
30 Nicolau-Junior N and Giuliatti S (2013) Modeling and molecular dynamics of the intrinsically disordered e7 proteins from high- and low-risk types of human papillomavirus. J Mol Model 19, 4025-4037   DOI
31 Marsh JA, Singh VK, Jia Z and Forman-Kay JD (2006) Sensitivity of secondary structure propensities to sequence differences between α- and γ-synuclein: Implications for fibrillation. Protein Sci 15, 2795-2804   DOI
32 O’Hare P and Williams G (1992) Structural studies of the acidic transactivation domain of the Vmw65 protein of herpes simplex virus using 1H NMR. Biochemistry 31, 4150-4156   DOI
33 Dahlman-Wright K, Baumann H, McEwan IJ et al (1995) Structural characterization of a minimal functional transactivation domain from the human glucocorticoid receptor. Proc Natl Acad Sci U S A 92, 1699-1703   DOI
34 Schneider R, Huang JR, Yao M et al (2012) Towards a robust description of intrinsic protein disorder using nuclear magnetic resonance spectroscopy. Mol Biosyst 8, 58-68   DOI
35 Neal S, Nip AM, Zhang H and Wishart DS (2003) Rapid and accurate calculation of protein 1H, 13C and 15N chemical shifts. J Biomol NMR 26, 215-240   DOI
36 Kim D-H, Lee C, Cho Y-J et al (2015) A pre-structured helix in the intrinsically disordered 4EBP1. Mol BioSyst 11, 366-369   DOI
37 Borcherds W, Theillet F-X, Katzer A et al (2014) Disorder and residual helicity alter p53-Mdm2 binding affinity and signaling in cells. Nat Chem Biol 10, 1000-1002   DOI
38 Iesmantavicius V, Dogan J, Jemth P, Teilum K and Kjaergaard M (2014) Helical propensity in an intrinsically disordered protein accelerates ligand binding. Angew Chem Int Ed 53, 1548-1551   DOI
39 Csizmók V, Szőllősi E, Friedrich P and Tompa P (2006) A novel two-dimensional electrophoresis technique for the identification of intrinsically unstructured proteins. Mol Cell Proteomics 5, 265-273   DOI