An order-to-disorder structural switch activates the FoxM1 transcription factor
| Autor: | Andrew C. McShan, Eefei Chen, Nikolaos G. Sgourakis, Caileen M Brison, Aimee H. Marceau, Heather E. Arsenault, Santrupti Nerli, Seth M. Rubin, Jennifer A. Benanti, Hsiau-Wei Lee |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Protein Conformation QH301-705.5 Sialoglycoproteins Structural Biology and Molecular Biophysics Cdk Science Cell Cycle Proteins Protein Serine-Threonine Kinases Intrinsically disordered proteins PLK1 General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Transactivation 0302 clinical medicine Protein Domains Cyclin-dependent kinase Proto-Oncogene Proteins transcription factors Phosphorylation Biology (General) Transcription factor General Immunology and Microbiology biology Activator (genetics) Chemistry General Neuroscience Forkhead Box Protein M1 General Medicine Peptide Fragments Cell biology Enzyme Activation nuclear magnetic resonance 030104 developmental biology Structural biology Plk1 030220 oncology & carcinogenesis biology.protein Medicine intrinsically disordered proteins Protein Processing Post-Translational Protein Binding Research Article Human |
| Zdroj: | eLife, Vol 8 (2019) eLife |
| Popis: | Intrinsically disordered transcription factor transactivation domains (TADs) function through structural plasticity, adopting ordered conformations when bound to transcriptional co-regulators. Many transcription factors contain a negative regulatory domain (NRD) that suppresses recruitment of transcriptional machinery through autoregulation of the TAD. We report the solution structure of an autoinhibited NRD-TAD complex within FoxM1, a critical activator of mitotic gene expression. We observe that while both the FoxM1 NRD and TAD are primarily intrinsically disordered domains, they associate and adopt a structured conformation. We identify how Plk1 and Cdk kinases cooperate to phosphorylate FoxM1, which releases the TAD into a disordered conformation that then associates with the TAZ2 or KIX domains of the transcriptional co-activator CBP. Our results support a mechanism of FoxM1 regulation in which the TAD undergoes switching between disordered and different ordered structures. |
| Databáze: | OpenAIRE |
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