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Regulation of apoptosis by an intrinsically disordered region of Bcl-xL.


ABSTRACT: Intrinsically disordered regions (IDRs) of proteins often regulate function upon post-translational modification (PTM) through interactions with folded domains. An IDR linking two ?-helices (?1-?2) of the antiapoptotic protein Bcl-xL experiences several PTMs that reduce antiapoptotic activity. Here, we report that PTMs within the ?1-?2 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.

SUBMITTER: Follis AV 

PROVIDER: S-EPMC5899648 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Regulation of apoptosis by an intrinsically disordered region of Bcl-xL.

Follis Ariele Viacava AV   Llambi Fabien F   Kalkavan Halime H   Yao Yong Y   Phillips Aaron H AH   Park Cheon-Gil CG   Marassi Francesca M FM   Green Douglas R DR   Kriwacki Richard W RW  

Nature chemical biology 20180305 5


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.  ...[more]

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