| Autor: |
Tatarskiy VV; Laboratory of Tumor Cell Death, N.N. Blokhin Russian Cancer Research Center, Kashirskoye Shosse 24, Moscow, 115478, Russia., Simonov YP; Department of Transcription Factors, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Str. 32, Moscow, 119991, Russia., Shcherbinin DS; Laboratory of Structure Bioinformatics, Institute of Biomedical Chemistry (IBMC), Pogodinskaya street 10 building 8, Moscow, 119121, Russia., Brechalov AV; Department of Transcription Factors, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Str. 32, Moscow, 119991, Russia., Georgieva SG; Department of Eukariotic Transcription Factors, Institute of Gene Biology, Russian Academy of Sciences, Vavilov Str. 34/5, Moscow, 119991, Russia. sonjag@molbiol.edu.ru.; Department of Transcription Factors, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Str. 32, Moscow, 119991, Russia. sonjag@molbiol.edu.ru., Soshnikova NV; Department of Eukariotic Transcription Factors, Institute of Gene Biology, Russian Academy of Sciences, Vavilov Str. 34/5, Moscow, 119991, Russia. so2615nat@gmail.com. |
| Abstrakt: |
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. |
