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

Aimee H Marceau,Seth M Rubin,Nikolaos G Sgourakis,Eefei Chen,Caileen M Brison,Jennifer A Benanti,Heather E Arsenault,Andrew C Mcshan,Hsiau-Wei Lee,Santrupti Nerli

doi:10.7554/elife.46131

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.

Highlights

The transactivation domains (TADs) of transcription factors are responsible for recruiting transcriptional machinery to target promoters (Ptashne and Gann, 1997)
Our results show that polo-like kinase 1 (Plk1) phosphorylation and not cyclin-dependent kinase (Cdk) directly inhibits the negative regulatory domain (NRD)-TAD association, yet strong evidence points to Cdk phosphorylation as an important step in the activation of FoxM1 during the cell cycle (Anders et al, 2011; Fu et al, 2008; Laoukili et al, 2008a; LuscherFirzlaff et al, 2006; Major et al, 2004; Park et al, 2008b; Wierstra and Alves, 2006a; Wierstra and Alves, 2006b)
Whereas structural disorder is required for function, it follows that the induction of structure could be used to negatively regulate transcription factor activity by restricting accessibility, of the transactivation domain

Summary

Introduction

The transactivation domains (TADs) of transcription factors are responsible for recruiting transcriptional machinery to target promoters (Ptashne and Gann, 1997). TADs consist of structurally disordered domains, which facilitate adaptable association with multiple protein partners and, in some contexts, form interaction network hubs within liquid condensates (Cho et al, 2018; Chong et al, 2018; Liu et al, 2006; Minezaki et al, 2006; Wright and Dyson, 2015). Considering their intrinsic disorder, it is critical to understand how TAD accessibility is restricted to regulate transcription factor activity. We find that the key phosphorylation-induced activation step is marked by a transition from structural order to disorder, which results in accessibility of the TAD for co-activator binding

Results

A P AA TAD

Discussion

Materials and methods