Abstract
Direct interaction between intrinsically disordered proteins (IDPs) is often difficult to characterize hampering the elucidation of their binding mechanism. Particularly challenging is the study of fuzzy complexes, in which the intrinsically disordered proteins or regions retain conformational freedom within the assembly. To date, nuclear magnetic resonance spectroscopy has proven to be one of the most powerful techniques to characterize at the atomic level intrinsically disordered proteins and their interactions, including those cases where the formed complexes are highly dynamic. Here, we present the characterization of the interaction between a viral protein, the Early region 1A protein from Adenovirus (E1A), and a disordered region of the human CREB-binding protein, namely the fourth intrinsically disordered linker CBP-ID4. E1A was widely studied as a prototypical viral oncogene. Its interaction with two folded domains of CBP was mapped, providing hints for understanding some functional aspects of the interaction with this transcriptional coactivator. However, the role of the flexible linker connecting these two globular domains of CBP in this interaction was never explored before.
Highlights
The adenovirus (AdV) is responsible for respiratory and gastric infections in humans and oncogenic transformation in rodents
We present the characterization of the interaction between a viral protein, the Early region 1A protein from Adenovirus (E1A), and a disordered region of the human CREB-binding protein, namely the fourth intrinsically disordered linker CBP-ID4
The early region 1A (E1A) gene is the first expressed following adenoviral infection and it plays a central role in viral function, activating the genes required for viral replication and interfering with the host cell cycle regulation [1,2]
Summary
The adenovirus (AdV) is responsible for respiratory and gastric infections in humans and oncogenic transformation in rodents. The interaction of fragments of E1A with the CBP-TAZ2 and CBP-NCBD single domains was investigated by NMR spectroscopy [28,29]. NMR was used to investigate the interaction of E1A with NCBD In this case, it was possible to estimate the binding affinity for the fragment E1A53–91 by NMR spectroscopy titration, obtaining a Kd = 1.0 μM for the N-terminus of E1A and Kd = 75 μM for E1A53–91 [29]. The interaction of the fragments of E1A with NCBD is weaker than the one with TAZ2, forming complexes that are in fast exchange with the isolated form on the NMR timescale. To advance our understanding of the mechanism through which E1A interferes with CBP function and the possible role of targeting its disordered domains, we investigated the interaction between E1A12S and the CBP-ID4 linker Can the linker between CBP-TAZ2 and CBP-NCBD be an additional target for E1A? To advance our understanding of the mechanism through which E1A interferes with CBP function and the possible role of targeting its disordered domains, we investigated the interaction between E1A12S and the CBP-ID4 linker
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