More Like this

1. Deciphering the Mystery in p300 Taz2–p53 TAD2 Recognition

   https://doi.org/10.1021/acs.jctc.4c00541  

   Li, Tongtong; Motta, Stefano; He, Yi (August 2024, Journal of Chemical Theory and Computation)

   Intrinsically disordered proteins (IDPs) engage in various fundamental biological activities, and their behavior is of particular importance for a better understanding of the verbose but well-organized signal transduction in cells. IDPs exhibit uniquely paradoxical features with low affinity but simultaneously high specificity in recognizing their binding targets. The transcription factor p53 plays a crucial role in cancer suppression, carrying out some of its biological functions using its disordered regions, such as N-terminal transactivation domain 2 (TAD2). Exploration of the binding and unbinding processes between proteins is challenging, and the inherently disordered properties of these regions further complicate the issue. Computer simulations are a powerful tool to complement the experiments to fill gaps to explore the binding/unbinding processes between proteins. Here, we investigated the binding mechanism between p300 Taz2 and p53 TAD2 through extensive molecular dynamics (MD) simulations using the physics- based UNited RESidue (UNRES) force field with additional Go̅-like potentials. Distance restraints extracted from the NMR- resolved structures were imposed on intermolecular residue pairs to accelerate binding simulations, in which Taz2 was immobilized in a native-like conformation and disordered TAD2 was fully free. Starting from six structures with TAD2 placed at different positions around Taz2, we observed a metastable intermediate state in which the middle helical segment of TAD2 is anchored in the binding pocket, highlighting the significance of the TAD2 helix in directing protein recognition. Physics-based binding simulations show that successful binding is achieved after a series of stages, including (1) protein collisions to initiate the formation of encounter complexes, (2) partial attachment of TAD2, and finally (3) full attachment of TAD2 to the correct binding pocket of Taz2. Furthermore, machine-learning-based PathDetect-SOM was used to identify two binding pathways, the encounter complexes, and the intermediate states. 

   more » « less
2. The E3 ligase RFWD3 stabilizes ORC in a p53-dependent manner

   https://doi.org/10.1080/15384101.2020.1829823  

   Hsu, Rosaline Y.C.; Giri, Sumanprava; Wang, Yating; Lin, Yo-Chuen; Liu, Dazhen; Wopat, Susan; Chakraborty, Arindam; Prasanth, Kannanganattu V.; Prasanth, Supriya G. (November 2020, Cell Cycle)

   null (Ed.)
3. Peptide and protein chemistry approaches to study the tumor suppressor protein p53

   https://doi.org/10.1039/D2OB00902A  

   Chatterjee, Champak; Singh, Sumeet K. (June 2022, Organic & Biomolecular Chemistry)

   The tumor suppressor and master gene regulator protein p53 has been the subject of intense investigation for several decades due to its mutation in about half of all human cancers. However, mechanistic studies of p53 in cells are complicated by its many dynamic binding partners and heterogeneous post-translational modifications. The design of therapeutics that rescue p53 functions in cells requires a mechanistic understanding of its protein–protein interactions in specific protein complexes and identifying changes in p53 activity by diverse post-translational modifications. This review highlights the important roles that peptide and protein chemistry have played in biophysical and biochemical studies aimed at elucidating p53 regulation by several key binding partners. The design of various peptide inhibitors that rescue p53 function in cells and new opportunities in targeting p53-protein interactions are discussed. In addition, the review highlights the importance of a protein semisynthesis approach to comprehend the role of site-specific PTMs in p53 regulation. 

   more » « less
4. Anomalous Dense Liquid Condensates Host the Nucleation of Tumor Suppressor p53 Fibrils

   https://doi.org/10.1016/j.isci.2019.01.027  

   Safari, Mohammad S.; Wang, Zhiqing; Tailor, Kunaal; Kolomeisky, Anatoly B.; Conrad, Jacinta C.; Vekilov, Peter G. (February 2019, iScience)
5. Mesoscopic protein-rich clusters host the nucleation of mutant p53 amyloid fibrils

   https://doi.org/10.1073/pnas.2015618118  

   Yang, David S.; Saeedi, Arash; Davtyan, Aram; Fathi, Mohsen; Sherman, Michael B.; Safari, Mohammad S.; Klindziuk, Alena; Barton, Michelle C.; Varadarajan, Navin; Kolomeisky, Anatoly B.; et al (March 2021, Proceedings of the National Academy of Sciences)

   The protein p53 is a crucial tumor suppressor, often called “the guardian of the genome”; however, mutations transform p53 into a powerful cancer promoter. The oncogenic capacity of mutant p53 has been ascribed to enhanced propensity to fibrillize and recruit other cancer fighting proteins in the fibrils, yet the pathways of fibril nucleation and growth remain obscure. Here, we combine immunofluorescence three-dimensional confocal microscopy of human breast cancer cells with light scattering and transmission electron microscopy of solutions of the purified protein and molecular simulations to illuminate the mechanisms of phase transformations across multiple length scales, from cellular to molecular. We report that the p53 mutant R248Q (R, arginine; Q, glutamine) forms, both in cancer cells and in solutions, a condensate with unique properties, mesoscopic protein-rich clusters. The clusters dramatically diverge from other protein condensates. The cluster sizes are decoupled from the total cluster population volume and independent of the p53 concentration and the solution concentration at equilibrium with the clusters varies. We demonstrate that the clusters carry out a crucial biological function: they host and facilitate the nucleation of amyloid fibrils. We demonstrate that the p53 clusters are driven by structural destabilization of the core domain and not by interactions of its extensive unstructured region, in contradistinction to the dense liquids typical of disordered and partially disordered proteins. Two-step nucleation of mutant p53 amyloids suggests means to control fibrillization and the associated pathologies through modifying the cluster characteristics. Our findings exemplify interactions between distinct protein phases that activate complex physicochemical mechanisms operating in biological systems. 

   more » « less