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Elife. 2019 May 28;8. pii: e46131. doi: 10.7554/eLife.46131.

An order-to-disorder structural switch activates the FoxM1 transcription factor.

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Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, United States.
Department of Computer Science, University of California, Santa Cruz, Santa Cruz, United States.
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, United States.
Contributed equally


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.


Cdk; Plk1; human; intrinsically disordered proteins; molecular biophysics; nuclear magnetic resonance; structural biology; transcription factors

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