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.
journal_name
Nat Chem Bioljournal_title
Nature chemical biologyauthors
Follis AV,Llambi F,Kalkavan H,Yao Y,Phillips AH,Park CG,Marassi FM,Green DR,Kriwacki RWdoi
10.1038/s41589-018-0011-xsubject
Has Abstractpub_date
2018-05-01 00:00:00pages
458-465issue
5eissn
1552-4450issn
1552-4469pii
10.1038/s41589-018-0011-xjournal_volume
14pub_type
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