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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.

Author information

1
Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, United States.
2
Department of Computer Science, University of California, Santa Cruz, Santa Cruz, United States.
3
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, United States.
#
Contributed equally

Abstract

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.

KEYWORDS:

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

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