The Heterogeneous Structural Behavior of E7 from HPV16 Revealed by NMR Spectroscopy

Calçada, Eduardo O.; Felli, Isabella C.; Hošek, Tomáš; Pierattelli, Roberta

doi:10.1002/cbic.201300172

Cited by 19 publications

(24 citation statements)

References 57 publications

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“…The 1 H- 15 N HSQC spectrum (Supplementary Figure S7) confirms that the 1-51 region of the full-length protein remains disordered, as in the E7(1-51) peptide, in agreement with earlier studies on full-length E7 from HPV16 and HPV45 [13, 15]. Cross peaks associated with the CR3 zinc finger dimerization domain are weak and broad (Figure S7).…”

Section: Resultssupporting

confidence: 88%

“…Cross peaks associated with the CR3 zinc finger dimerization domain are weak and broad (Figure S7). Concentration- and pH-dependent broadening of the CR3 resonances in full-length HPV16 E7 has recently been reported and has been attributed to flexibility and aggregation of the CR3 domain [13, 14]. Since the cross peaks for most residues in the CR1 and CR2 regions appear to coincide in the spectra of the peptide and the full length protein, and since the pulldown results were the same for E7(1-98) and E7(1-51) (Figure 1c, d), we deduced that the N-terminal region of the protein remained similarly disordered in the shorter construct and the full-length protein.…”

Section: Resultsmentioning

confidence: 99%

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The High-Risk HPV16 E7 Oncoprotein Mediates Interaction between the Transcriptional Coactivator CBP and the Retinoblastoma Protein pRb

Jansma

Martinez-Yamout

Long

et al. 2014

Journal of Molecular Biology

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The oncoprotein E7 from human papillomavirus (HPV) strains that confer high cancer risk mediates cell transformation by deregulating host cellular processes and activating viral gene expression through recruitment of cellular proteins such as the retinoblastoma protein (pRb) and the CREB-binding protein (CBP) and its paralog p300. Here we show that the intrinsically disordered N-terminal region of E7 from high risk HPV16 binds the TAZ2 domain of CBP with greater affinity than E7 from low risk HPV6b. HPV E7 and the tumor suppressor p53 compete for binding to TAZ2. The TAZ2 binding site in E7 overlaps the LxCxE motif that is crucial for interaction with pRb. While TAZ2 and pRb compete for binding to a monomeric E7 polypeptide, the full-length E7 dimer mediates an interaction between TAZ2 and pRb by promoting formation of a ternary complex. Cell-based assays show that expression of full-length HPV16 E7 promotes increased pRb acetylation and that this response depends both on the presence of CBP/p300 and the ability of E7 to form a dimer. These observations suggest a model for the oncogenic effect of high risk HPV16-E7. The disordered region of one E7 molecule in the homodimer interacts with the pocket domain of pRb, while the same region of the other E7 molecule binds the TAZ2 domain of CBP/p300. Through its ability to dimerize, E7 recruits CBP/p300 and pRb into a ternary complex, bringing the histone acetyltransferase domain of CBP/p300 into proximity to pRb and promoting acetylation, leading to disruption of cell cycle control.

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Section: Resultssupporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

The High-Risk HPV16 E7 Oncoprotein Mediates Interaction between the Transcriptional Coactivator CBP and the Retinoblastoma Protein pRb

Jansma

Martinez-Yamout

Long

et al. 2014

Journal of Molecular Biology

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“…The CR1 and CR2 regions of E7 are intrinsically disordered (91,92), whereas CR3 is a zinc binding domain that mediates formation of a homodimer (93,94). The disordered CR1 and CR2 regions of E7 from high risk HPV16 bind with high affinity to the TAZ2 domain of CBP (95).…”

Section: Viral Idps Compete With Cellular Proteins For Cbp/p300 Bindingmentioning

confidence: 99%

Role of Intrinsic Protein Disorder in the Function and Interactions of the Transcriptional Coactivators CREB-binding Protein (CBP) and p300

Dyson

Wright

2016

Journal of Biological Chemistry

284

270

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The transcriptional coactivators CREB-binding protein (CBP) and p300 undergo a particularly rich set of interactions with disordered and partly ordered partners, as a part of their ubiquitous role in facilitating transcription of genes. CBP and p300 contain a number of small structured domains that provide scaffolds for the interaction of disordered transactivation domains from a wide variety of partners, including p53, hypoxiainducible factor 1␣ (HIF-1␣), NF-B, and STAT proteins, and are the targets for the interactions of disordered viral proteins that compete with cellular factors to disrupt signaling and subvert the cell cycle. The functional diversity of the CBP/p300 interactome provides an excellent example of the power of intrinsic disorder to facilitate the complexity of living systems.

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“…The E7 N terminus is intrinsically disordered and flexible, perhaps accounting for its promiscuous binding abilities (Heck, Yee et al 1992; Calcada, Felli et al 2013; Lee, Kim et al 2016). The N terminus includes both CR1 and CR2.…”

Section: Introductionmentioning

confidence: 99%

The human papillomavirus E7 oncoprotein as a regulator of transcription

2017

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High-risk human papillomaviruses (HPVs) encode oncoproteins which manipulate gene expression patterns in the host keratinocytes to facilitate viral replication, regulate viral transcription, and promote immune evasion and persistence. In some cases, oncoprotein-induced changes in host cell behavior can cause progression to cancer, but a complete picture of the functions of the viral oncoproteins in the productive HPV life cycle remains elusive. E7 is the HPV-encoded factor most responsible for maintaining cell cycle competence in differentiating keratinocytes. Through interactions with dozens of host factors, E7 has an enormous impact on host gene expression patterns. In this review, we will examine the role of E7 specifically as a regulator of transcription. We will discuss mechanisms of regulation of cell cycle-related genes by E7 as well as genes involved in immune regulation, growth factor signaling, DNA damage responses, microRNAs, and others pathways. We will also discuss some unanswered questions about how transcriptional regulation by E7 impacts the biology of HPV in both benign and malignant conditions.

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The Heterogeneous Structural Behavior of E7 from HPV16 Revealed by NMR Spectroscopy

Cited by 19 publications

References 57 publications

The High-Risk HPV16 E7 Oncoprotein Mediates Interaction between the Transcriptional Coactivator CBP and the Retinoblastoma Protein pRb

The High-Risk HPV16 E7 Oncoprotein Mediates Interaction between the Transcriptional Coactivator CBP and the Retinoblastoma Protein pRb

Role of Intrinsic Protein Disorder in the Function and Interactions of the Transcriptional Coactivators CREB-binding Protein (CBP) and p300

The human papillomavirus E7 oncoprotein as a regulator of transcription

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