Intrinsic Structural Disorder in Adenovirus E1A: a Viral Molecular Hub Linking Multiple Diverse Processes

Pelka, Peter; Ablack, Jailal; Fonseca, Gregory J.; Yousef, Ahmed F.; Mymryk, Joe S.

doi:10.1128/jvi.00104-08

Cited by 133 publications

(192 citation statements)

References 147 publications

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“…S2B). Thus, the NMR spectra are consistent with recent predictions that, except for CR3, E1A is intrinsically disordered (43). There are 4 known binding motifs located between residues 1 and 139 of E1A; residues 1-25 (13,(27)(28)(29) and residues 54-83 (this work) form binding sites for CBP/p300, while residues 37-51 (CR1) and 121-129 (CR2) function in pRb binding.…”

Section: Structural Model Of the Ternary Complexsupporting

confidence: 76%

“…5C); the CR1-CR2 linker must be long enough to allow simultaneous binding of CR1 and CR2 in their cognate sites on pRb and to accommodate binding of CBP/p300 without creating steric clashes. CR1 and CR2 are connected by a long (Ͼ30 residues) intrinsically disordered linker (43) (Fig. S2B) in all sequenced E1A serotypes (37).…”

Section: Structural Model Of the Ternary Complexmentioning

confidence: 99%

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Structural basis for subversion of cellular control mechanisms by the adenoviral E1A oncoprotein

Ferreon

Martinez-Yamout²,

Dyson³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

119

186

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The adenovirus early region 1A (E1A) oncoprotein mediates cell transformation by deregulating host cellular processes and activating viral gene expression by recruitment of cellular proteins that include cyclic-AMP response element binding (CREB) binding protein (CBP)/p300 and the retinoblastoma protein (pRb). While E1A is capable of independent interaction with CBP/p300 or pRb, simultaneous binding of both proteins is required for maximal biological activity. To obtain insights into the mechanism by which E1A hijacks the cellular transcription machinery by competing with essential transcription factors for binding to CBP/p300, we have determined the structure of the complex between the transcriptional adaptor zinc finger-2 (TAZ2) domain of CBP and the conserved region-1 (CR1) domain of E1A. The E1A CR1 domain is unstructured in the free state and upon binding folds into a local helical structure mediated by an extensive network of intermolecular hydrophobic contacts. By NMR titrations, we show that E1A efficiently competes with the N-terminal transactivation domain of p53 for binding to TAZ2 and that pRb interacts with E1A at 2 independent sites located in CR1 and CR2. We show that pRb and the CBP TAZ2 domain can bind simultaneously to the CR1 site of E1A to form a ternary complex and propose a structural model for the pRb:E1A:CBP complex on the basis of published x-ray data for homologous binary complexes. These observations reveal the molecular basis by which E1A inhibits p53-mediated transcriptional activation and provide a rationale for the efficiency of cellular transformation by the adenoviral E1A oncoprotein.CBP/p300 ͉ NMR ͉ protein structure ͉ transcriptional coactivator ͉ retinoblastoma protein T he adenovirus early region 1A (E1A) protein plays a central function in viral infection by activating genes required for viral replication and by deregulating the host cell cycle to force entry into S phase and repress differentiation (1-3). E1A deregulates the cell cycle through interactions with key cellular proteins, including the general transcriptional coactivators cyclic-AMP response element binding (CREB) binding protein (CBP) and p300 (4, 5) and the retinoblastoma protein (pRb) (6), which lead to epigenetic modifications and reprogramming of host cell transcriptional processes (7). Binding of E1A to pRb displaces the E2F transcription factors, thereby relieving E2F repression and resulting in premature S-phase entry and transcriptional activation of E2F-regulated genes (8-10). Association of E1A with CBP/p300 results in global hypoacetylation of K18 of histone H3 and may be linked to the ability of E1A to induce oncogenic transformation (11). E1A is a multifunctional protein (12) composed of 4 conserved regions (CR1-CR4, Fig. 1A). E1A uses both CR1 and CR2 for interaction with pRb (13,14). CR2 contains a characteristic pRb recognition motif, LX-CXE, which binds with high affinity to the B cyclin fold domain of the pRb pocket region (15, 16). The CR1 region of E1A binds at the interface of the A and B ...

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Section: Structural Model Of the Ternary Complexsupporting

confidence: 76%

Section: Structural Model Of the Ternary Complexmentioning

confidence: 99%

Structural basis for subversion of cellular control mechanisms by the adenoviral E1A oncoprotein

Ferreon

Martinez-Yamout²,

Dyson³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

119

186

View full text Add to dashboard Cite

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“…Mimicry of this interaction by a viral oncogene such as E1A is highly suggestive of the fact that this module in the cellular interaction network is vitally important. Our data also set the stage for determining the specific biological consequences of a reduction in polySUMOylation and suggest that E1A could be a useful reagent in these studies, as it has been for other cellular proteins, such as pRb, p300/CBP and CtBP (Pelka et al, 2008). It is intriguing that this UBC9-binding MoRF that we identified in E1A seems to be present in cellular proteins, suggesting that they may similarly influence polySUMOylation.…”

Section: E1a Interaction With Ubc9mentioning

confidence: 63%

“…Oncogenic transformation directly reflects the fundamental changes made to the cellular protein interaction network by virally encoded hub proteins in the infected cell. E1A is a key molecular hub in HAd (Frisch and Mymryk, 2002;Pelka et al, 2008). Sequence comparisons of the E1A proteins of numerous HAds identified four regions of sequence similarity, designated CR1-4 (Avvakumov et al, 2002(Avvakumov et al, , 2004.…”

Section: Introductionmentioning

confidence: 99%

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Identification of a molecular recognition feature in the E1A oncoprotein that binds the SUMO conjugase UBC9 and likely interferes with polySUMOylation

et al. 2010

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Hub proteins have central roles in regulating cellular processes. By targeting a single cellular hub, a viral oncogene may gain control over an entire module in the cellular interaction network that is potentially comprised of hundreds of proteins. The adenovirus E1A oncoprotein is a viral hub that interacts with many cellular hub proteins by short linear motifs/molecular recognition features (MoRFs). These interactions transform the architecture of the cellular protein interaction network and virtually reprogram the cell. To identify additional MoRFs within E1A, we screened portions of E1A for their ability to activate yeast pseudohyphal growth or differentiation. This identified a novel functional region within E1A conserved region 2 comprised of the sequence EVIDLT. This MoRF is necessary and sufficient to bind the N-terminal region of the SUMO conjugase UBC9, which also interacts with SUMO noncovalently and is involved in polySUMOylation. Our results suggest that E1A interferes with polySUMOylation, but not with monoSUMOylation. These data provide the first insight into the consequences of the interaction of E1A with UBC9, which was initially described in 1996. We further demonstrate that polySUMOylation regulates pseudohyphal growth and promyelocytic leukemia body reorganization by E1A. In conclusion, the interaction of the E1A oncogene with UBC9 mimics the normal binding between SUMO and UBC9 and represents a novel mechanism to modulate polySUMOylation.

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Viral and cellular interactions during adenovirus DNA replication

2019

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Intrinsic Structural Disorder in Adenovirus E1A: a Viral Molecular Hub Linking Multiple Diverse Processes

Cited by 133 publications

References 147 publications

Structural basis for subversion of cellular control mechanisms by the adenoviral E1A oncoprotein

Structural basis for subversion of cellular control mechanisms by the adenoviral E1A oncoprotein

Identification of a molecular recognition feature in the E1A oncoprotein that binds the SUMO conjugase UBC9 and likely interferes with polySUMOylation

Viral and cellular interactions during adenovirus DNA replication

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