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Open AccessArticle

Probing the Protein-Protein Interaction between the ATRXADD Domain and the Histone H3 Tail

Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Rd, Storrs, CT 06029-3092, USA
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Molecules 2020, 25(7), 1500; https://doi.org/10.3390/molecules25071500
Received: 19 February 2020 / Revised: 12 March 2020 / Accepted: 23 March 2020 / Published: 25 March 2020
(This article belongs to the Special Issue Probing New and Underexplored Protein-Protein Interactions)
While loss-of-function mutations in the ATRX gene have been implicated as a driving force for a variety of pediatric brain tumors, as well as pancreatic neuroendocrine tumors, the role of ATRX in gene regulation and oncogenic development is not well-characterized. The ADD domain of ATRX (ATRXADD) localizes the protein to chromatin by specifically binding to the histone H3 tail. This domain is also a primary region that is mutated in these cancers. The overall goal of our studies was to utilize a variety of techniques (experimental and computational) to probe the H3:ATRXADD protein-protein interaction (PPI). We developed two biochemical assays that can be utilized to study the interaction. These assays were utilized to experimentally validate and expand upon our previous computational results. We demonstrated that the three anchor points in the H3 tail (A1, K4, and K9) are all essential for high affinity binding and that disruption of more than one contact region will be required to develop a small molecule that disrupts the PPI. Our approach in this study could be applied to other domains of ATRX, as well as PPIs between other distinct proteins. View Full-Text
Keywords: protein-protein interactions; cancer; isothermal titration calorimetry; virtual screening; fluorescence polarization; AlphaScreen protein-protein interactions; cancer; isothermal titration calorimetry; virtual screening; fluorescence polarization; AlphaScreen
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Zaino, A.M.; Dash, R.C.; Hadden, M.K. Probing the Protein-Protein Interaction between the ATRXADD Domain and the Histone H3 Tail. Molecules 2020, 25, 1500.

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