Human TFIID Binds to Core Promoter DNA in a Reorganized Structural State

A mechanistic description of metazoan transcription is essential for understanding the molecular processes that govern cellular decisions. To provide structural insights into the DNA recognition step of transcription initiation, we used single-particle electron microscopy (EM) to visualize human TFIID with promoter DNA. This analysis revealed that TFIID coexists in two predominant and distinct structural states that differ by a 100 Å translocation of TFIID’s lobe A. The transition between these structural states is modulated by TFIIA, as the presence of TFIIA and promoter DNA facilitates the formation of a rearranged state of TFIID that enables promoter recognition and binding. DNA labeling and footprinting, together with cryo-EM studies, were used to map the locations of TATA, Initiator (Inr), motif ten element (MTE), and downstream core promoter element (DPE) promoter motifs within the TFIID-TFIIA-DNA structure. The existence of two structurally and functionally distinct forms of TFIID suggests that the different conformers may serve as specific targets for the action of regulatory factors. [Display omitted] ► TFIID has distinct conformations with different positions of the TBP-containing lobe ► A rearranged state of TFIID interacts with promoter DNA in a TFIIA-dependent manner ► TFIID induces multiple topological changes on promoter DNA around the start site ► The different conformations of TFIID may serve as targets for regulatory factors TFIID undergoes a radical structural rearrangement when it binds promoter DNA. The bound form identified in this study defines TFIID’s interaction with the upstream and downstream core promoter regions during a key step in transcription initiation.