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<p>Hexim proteins are key RNA-dependent regulators of eukaryotic transcription through 7SK-dependent sequestration and inactivation of the kinase P-TEFb (Cdk9–CyclinT1/2) in the 7SK RNP. P-TEFb activity drives release of RNA polymerase II from promoter-proximal pausing for eukaryotic and HIV-1 transcription. The molecular mechanism by which 7SK binding overcomes an intrinsic Hexim autoinhibition for subsequent P-TEFb inactivation has remained unresolved. Here, using NMR and biophysical methods we demonstrate that Hexim1 homodimer engages two high-affinity sites on 7SK RNA. This dual-site binding triggers a conformational rearrangement in Hexim1’s disordered central region that unmasks the Cdk9-binding site, which is otherwise sequestered within an inter-monomer dimer interface. These findings reveal how Hexim autoinhibition dictates its specificity for 7SK RNA and prevents premature P-TEFb inhibition in the absence of 7SK, thereby providing a mechanistic understanding of Hexim/P-TEFb assembly into the 7SK RNP and further considerations for understanding Hexim–Tat competition during viral transcription.</p>

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HEXIM1 inter-monomer autoinhibition governs 7SK RNA binding specificity and P-TEFb inactivation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月15日

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  • Yuan Yang,
  • Maria Grazia Murrali,
  • Sabrina Galvan,
  • Yaqiang Wang,
  • Christine Stephen,
  • Neha Ajjampore,
  • Xiaoyu Wang,
  • Juli Feigon

摘要

Hexim proteins are key RNA-dependent regulators of eukaryotic transcription through 7SK-dependent sequestration and inactivation of the kinase P-TEFb (Cdk9–CyclinT1/2) in the 7SK RNP. P-TEFb activity drives release of RNA polymerase II from promoter-proximal pausing for eukaryotic and HIV-1 transcription. The molecular mechanism by which 7SK binding overcomes an intrinsic Hexim autoinhibition for subsequent P-TEFb inactivation has remained unresolved. Here, using NMR and biophysical methods we demonstrate that Hexim1 homodimer engages two high-affinity sites on 7SK RNA. This dual-site binding triggers a conformational rearrangement in Hexim1’s disordered central region that unmasks the Cdk9-binding site, which is otherwise sequestered within an inter-monomer dimer interface. These findings reveal how Hexim autoinhibition dictates its specificity for 7SK RNA and prevents premature P-TEFb inhibition in the absence of 7SK, thereby providing a mechanistic understanding of Hexim/P-TEFb assembly into the 7SK RNP and further considerations for understanding Hexim–Tat competition during viral transcription.