Monté Didier, Lens Zoé, Dewitte Frédérique, Fislage Marcus, Aumercier Marc, Verger Alexis, Villeret Vincent
CNRS EMR 9002 Integrative Structural Biology, Inserm U 1167 - RID-AGE, Univ. Lille, CHU Lille, Institut Pasteur de Lille, Lille, France.
Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, Brussels, Belgium.
Nat Commun. 2025 Apr 22;16(1):3772. doi: 10.1038/s41467-025-59014-8.
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 PSIHFWSTLSP containing one phosphorylated residue (S383), 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.
中介体复合物亚基MED23的一个功能是响应Ras-MAPK信号通路，介导磷酸化转录因子Elk-1的转录激活。我们使用低温电子显微镜解析了与Elk-1磷酸化激活结构域复合的人源MED23的3.0埃结构。Elk-1通过包含一个磷酸化残基（S383）的疏水序列PSIHFWSTLSP与MED23结合，该序列围绕中心苯丙氨酸形成紧密的转角。Elk-1的结合诱导MED23发生变构变化，并传播到亚基的相对面，导致一个19个残基片段的动态行为，从而改变了MED23的分子表面。我们设计了一个特定的MED23突变（G382F），该突变破坏了Elk-1的结合，从而损害了Ras-Raf-MEK-ERK信号通路中Elk-1依赖的血清诱导的靶基因激活。该结构提供了关于中介体亚基-转录因子界面的分子细节和见解。
