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Review
. 2020 Oct 1;34(19-20):1287-1303.
doi: 10.1101/gad.341156.120.

The SAGA chromatin-modifying complex: the sum of its parts is greater than the whole

Jelly H M Soffers  1 , Jerry L Workman  1
Affiliations
Review

The SAGA chromatin-modifying complex: the sum of its parts is greater than the whole

Jelly H M Soffers et al. Genes Dev. .

Abstract

There are many large protein complexes involved in transcription in a chromatin context. However, recent studies on the SAGA coactivator complex are generating new paradigms for how the components of these complexes function, both independently and in concert. This review highlights the initial discovery of the canonical SAGA complex 23 years ago, our evolving understanding of its modular structure and the relevance of its modular nature for its coactivator function in gene regulation.

Keywords: DUB; HAT; SAGA; activators; adaptor complex; adaptors; chromatin; coactivator; structure; transcription.

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Figures

Figure 1.
Figure 1.
Schematic overview of the architecture of the SAGA complex based on electron microscopy, immunolabeling, and cross-linking mass spectrometry techniques. (A) The first S. cerevisiae SAGA structure divides it in five domains (adapted from Wu et al. 2004, with permission from Elsevier). Tra1 occupies domain I, and domains II–IV contain TAFs, core (Ada1, Spt7, and Spt20) and HAT subunits (Gcn5). Domain V is flexible and contains Spt3. (B) The subsequent SAGA structure locates the DUB module as bulging density in close proximity to TAF and Spt subunits. (Adapted from research originally published in Setiaputra et al. 2015. © the American Society for Biochemistry and Molecular Biology). This structure highly resembles the previous structure (Wu et al. 2004), when domain V is flipped toward domain I. The Spt subunits form a TBP-binding surface adjacent to Tra1, and the DUB and HAT modules locate to the right. Vertical dashes indicate the midplane. Subunit Spt3 and the DUB module are located on the backside. (C) Cryo-EM structure showing the narrow hinge region that forms the peripheral connection between Tra1 and the core modules (arrow; Tra1 cross-links to Spt20 and Taf12). The DUB (purple) and HAT module (yellow) associate with the structural core (green/white). The vertical stripes indicate the midplane. The DUB module anchors via the backside. Both enzymatic modules form a clamp that engages nucleosomes, and the HAT module can swirl ∼15° toward the DUB module (dashed arrow) (adapted from Cheung and Díaz-Santín 2019). (D) The architectural map determined by cross-linking mass spectrometry (adapted with permission from Han et al. 2014; © 2014 The Authors) reveals the close proximity of Tra1 and the Spt subunits, and the peripheral connections of Tra1 to the rest of the complex. The TAFs with Ada1 assume a central position and are interlinked with Spt subunits. The HAT and DUB module link to the TAF/Ada1 center, and the DUB module cross-links also to Spt20.
Figure 2.
Figure 2.
Modular division of the SAGA complex. (A) combinatorial depletion study in S. cerevisiae reveals the interprotein relationships of the complete SAGA complex. SAGA is divided into four modules that are conserved in Drosophila and humans. S. cerevisiae names are listed in the cartoon, and Drosophila and human paralogs are listed in the expanded boxes that are color-coded after their corresponding module. The four modules are the HAT module, the DUB module, TAF module, and Spt module. Note that Spt8 is not conserved in Drosophila and humans. (B) New modular division. The latest cryo-EM structure of SAGA in S. cerevisiae and P. pastori form a framework to further understand the relationship between subunits and the function of these subunits (Papai et al. 2020; Wang et al. 2020). The large, peripheral protein Tra1 is now considered its own module. The core module is composed of the former Spt and TAF module joint together. TAF and Spt proteins form an asymmetric octamer via histone fold dimer pairs (indicated with black lines). Spt20 is interwoven through the core and connects peripherally with Tra1. Spt20 and Taf12 anchor Tra1. Taf5 organizes the structure of the core and regulates the interactions of the Taf6/Taf9 dimer pair. The structure of the SAGA core allows for a flexible insertion of the two enzymatic modules.
Figure 3.
Figure 3.
Anchor points for the enzymatic modules of the SAGA complex (A) Front view. PDB ID 6T9I and stylized cartoon. (B) Back view. (C) Back view close-up showing the insertion of Sgf73. (PDB ID 6T9I) (Wang et al. 2020). The DUB module connects via the insertion the C-terminal part of Sgf73, which enters the core proximal to the Taf9 histone fold, traverses an elongated domain of Ada1, and exits next to the Spt20 SEP domain (Papai et al. 2020; Wang et al. 2020). Spt20 is critical for the association of the DUB module. The HAT module docks to SAGA at subunit Taf6, where two helical domains—attributable to Ada3—lie at the surface of the Taf6 HEAT repeat domain. Taf5, Ta6, and Taf9 likely stabilize the configuration of Taf6 as well as the overall structure of the core module. The conformations of the enzymatic modules are dynamic in vivo, and this mobility allows the modifications on a stretch of nucleosomal histone tails up along the promoter region.
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