Abstract
Intrinsically disordered regions (IDRs) of proteins often regulate function upon post-translational modification (PTM) through interactions with folded domains. An IDR linking two α-helices (α1-α2) of the antiapoptotic protein Bcl-xL experiences several PTMs that reduce antiapoptotic activity. Here, we report that PTMs within the α1-α2 IDR promote its interaction with the folded core of Bcl-xL that inhibits the proapoptotic activity of two types of regulatory targets, BH3-only proteins and p53. This autoregulation utilizes an allosteric pathway whereby, in one direction, the IDR induces a direct displacement of p53 from Bcl-xL coupled to allosteric displacement of simultaneously bound BH3-only partners. This pathway operates in the opposite direction when the BH3-only protein PUMA binds to the BH3 binding groove of Bcl-xL, directly displacing other bound BH3-only proteins, and allosterically remodels the distal site, displacing p53. Our findings show how an IDR enhances functional versatility through PTM-dependent allosteric regulation of a folded protein domain.
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Acknowledgements
The authors acknowledge C.R. Grace (St. Jude Children’s Research Hospital, SJCRH) for assistance with NMR experiments and B. Cassell and P. Rodrigues (SJCRH) for peptide synthesis. This work was supported by NIH R01CA082491 and 1R01GM083159 (to R.W.K.); R01GM96208 (to D.R.G.); R01 CA179087 and R35 GM118186 (to F.M.M.); National Cancer Institute Cancer Center Support grants P30CA21765 (to SJCRH) and P30CA030199 (to S.B.P.); and ALSAC (to SJCRH). A.V.F. was the recipient of the Neoma Boadway Fellowship from SJCRH.
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A.V.F. designed experiments, performed experiments, analyzed data and wrote the manuscript; F.L. designed and performed cell experiments; H.K. designed experiments, performed experiments, and analyzed data; Y.Y. designed experiments, performed experiments, and analyzed data; A.H.P. designed experiments, performed experiments, and analyzed data; C.-G.P. and F.M.M. designed experiments and analyzed data; D.R.G. designed experiments and wrote the manuscript; and R.W.K. designed experiments, analyzed data and wrote the manuscript. All authors reviewed and edited the manuscript.
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Follis, A.V., Llambi, F., Kalkavan, H. et al. Regulation of apoptosis by an intrinsically disordered region of Bcl-xL. Nat Chem Biol 14, 458–465 (2018). https://doi.org/10.1038/s41589-018-0011-x
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DOI: https://doi.org/10.1038/s41589-018-0011-x
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