| Autor: |
Follis AV; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Llambi F; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.; Blueprint Medicines, Cambridge, MA, USA., Kalkavan H; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA., Yao Y; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Phillips AH; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Park CG; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Marassi FM; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Green DR; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA., Kriwacki RW; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA. richard.kriwacki@stjude.org.; Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Sciences Center, Memphis, TN, USA. richard.kriwacki@stjude.org. |
| Abstrakt: |
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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