Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Cambridge, MA 02139, USA.
Mol Cell. 2024 Jun 20;84(12):2238-2254.e11. doi: 10.1016/j.molcel.2024.05.017. Epub 2024 Jun 12.
Transcriptional coregulators and transcription factors (TFs) contain intrinsically disordered regions (IDRs) that are critical for their association and function in gene regulation. More recently, IDRs have been shown to promote multivalent protein-protein interactions between coregulators and TFs to drive their association into condensates. By contrast, here we demonstrate how the IDR of the corepressor LSD1 excludes TF association, acting as a dynamic conformational switch that tunes repression of active cis-regulatory elements. Hydrogen-deuterium exchange shows that the LSD1 IDR interconverts between transient open and closed conformational states, the latter of which inhibits partitioning of the protein's structured domains with TF condensates. This autoinhibitory switch controls leukemic differentiation by modulating repression of active cis-regulatory elements bound by LSD1 and master hematopoietic TFs. Together, these studies unveil alternative mechanisms by which disordered regions and their dynamic crosstalk with structured regions can shape coregulator-TF interactions to control cis-regulatory landscapes and cell fate.
转录共激活因子和转录因子 (TFs) 含有内在无序区域 (IDR)，这对于它们在基因调控中的结合和功能至关重要。最近，IDR 已被证明可以促进共激活因子和 TFs 之间的多价蛋白-蛋白相互作用，从而将它们的结合驱动到液滴中。相比之下，在这里我们展示了核心抑制剂 LSD1 的 IDR 如何排除 TF 的结合，作为一种动态构象开关，调节对活性顺式调控元件的抑制。氢氘交换表明 LSD1 IDR 在瞬时开放和关闭构象状态之间相互转换，后者抑制了蛋白质结构域与 TF 液滴的分区。这种自动抑制开关通过调节 LSD1 和主要造血 TF 结合的活性顺式调控元件的抑制来控制白血病分化。总之，这些研究揭示了无序区域及其与结构区域的动态相互作用可以塑造共激活因子-TF 相互作用，从而控制顺式调控景观和细胞命运的替代机制。
