Structural basis of human Mediator recruitment by the phosphorylated transcription factor Elk-1

Didier Monté (), Zoé Lens, Frédérique Dewitte, Marcus Fislage, Marc Aumercier, Alexis Verger () and Vincent Villeret ()
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Didier Monté: Institut Pasteur de Lille
Zoé Lens: Institut Pasteur de Lille
Frédérique Dewitte: Institut Pasteur de Lille
Marcus Fislage: Pleinlaan 2
Marc Aumercier: Institut Pasteur de Lille
Alexis Verger: Institut Pasteur de Lille
Vincent Villeret: Institut Pasteur de Lille

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract One function of Mediator complex subunit MED23 is to mediate transcriptional activation by the phosphorylated transcription factor Elk-1, in response to the Ras-MAPK signaling pathway. Using cryogenic electron microscopy, we solve a 3.0 Å structure of human MED23 complexed with the phosphorylated activation domain of Elk-1. Elk-1 binds to MED23 via a hydrophobic sequence PSIHFWSTLSPP containing one phosphorylated residue (S383p), which forms a tight turn around the central Phenylalanine. Binding of Elk-1 induces allosteric changes in MED23 that propagate to the opposite face of the subunit, resulting in the dynamic behavior of a 19-residue segment, which alters the molecular surface of MED23. We design a specific MED23 mutation (G382F) that disrupts Elk­-1 binding and consequently impairs Elk-1-dependent serum-induced activation of target genes in the Ras-Raf-MEK-ERK signaling pathway. The structure provides molecular details and insights into a Mediator subunit-transcription factor interface.

Date: 2025
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DOI: 10.1038/s41467-025-59014-8

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