Abstract

The PBAF chromatin-remodeling complexes are multi-protein machines, regulating expression of genes involved in proliferation and differentiation. PHF10 is a subunit of the PBAF essential for its association with chromatin. Mammalian PHF10 is expressed as four ubiquitous isoforms, which are alternatively incorporated in the complex and differ by their influence on transcription of target genes. PHF10 have different domain structure and two of them (PHF10-S isoforms) lack C-terminal PHD domains, which enables their phosphorylation by CK-1. Here we have found that PBAF subunits have low turnover rate, except for PHF10 which has much lower half-life, and is degraded by β-TrCP. The β-TrCP knockdown stabilizes PBAF core subunits - BRG1 and BAF155 and specific subunits - PHF10, BAF200, BAF180 and BRD7. PHF10 isoforms contain two non-canonical β-TrCP degrons and are degraded by β-TrCP in a phospho-dependent manner. But phosphorylation of PHF10-S degrons by CK-1, contrary to previously described degrons, prevents their degradation. Targeted molecular docking demonstrated that phosphorylated forms of PHF10 bind to β-TrCP with much lower affinity than non-phosphorylated ones, contrary to previously described degrons. This unorthodox mechanism proposes that phosphorylation of β-TrCP degrons by CK-1 could not only degrade a set of proteins, but also stabilize a different set of targets.

Details

Title
Stability of the PHF10 subunit of PBAF signature module is regulated by phosphorylation: role of β-TrCP
Author
Tatarskiy, Victor V 1   VIAFID ORCID Logo  ; Simonov, Yuriy P 2 ; Shcherbinin, Dmitrii S 3 ; Brechalov, Alexander V 2 ; Georgieva, Sofia G 4 ; Soshnikova, Nataliya V 5 

 Laboratory of Tumor Cell Death, N.N. Blokhin Russian Cancer Research Center, Moscow, Russia 
 Department of Transcription Factors, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia 
 Laboratory of Structure Bioinformatics, Institute of Biomedical Chemistry (IBMC), Moscow, Russia 
 Department of Eukariotic Transcription Factors, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia; Department of Transcription Factors, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia 
 Department of Eukariotic Transcription Factors, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia 
Pages
1-14
Publication year
2017
Publication date
Jul 2017
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
1956157244
Copyright
© 2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.