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Review
. 2011 Dec;21(6):767-74.
doi: 10.1016/j.sbi.2011.09.004. Epub 2011 Oct 18.

A new chapter in the transcription SAGA

Nadine L Samara  1 , Cynthia Wolberger
Affiliations
Review

A new chapter in the transcription SAGA

Nadine L Samara et al. Curr Opin Struct Biol. 2011 Dec.

Abstract

Eukaryotic transcriptional coactivators are multi-subunit complexes that both modify chromatin and recognize histone modifications. Until recently, structural information on these large complexes has been limited to isolated enzymatic domains or chromatin-binding motifs. This review summarizes recent structural studies of the SAGA coactivator complex that have greatly advanced our understanding of the interplay between its different subunits. The structure of the four-protein SAGA deubiquitinating module has provided a first glimpse of the larger organization of a coactivator complex, and illustrates how interdependent subunits interact with each other to form an active and functional enzyme complex. In addition, structures of the histone binding domains of ATXN7 and Sgf29 shed light on the interactions with chromatin that help recruit the SAGA complex.

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Figures

Figure 1
Figure 1. SAGA is a modular complex
The 21 yeast SAGA proteins are arranged into four distinct modules: The HAT module (green) consists of Ada3, Ada2, Sgf29 and the histone acetyltransferase (HAT) Gcn5. The DUB module (red) consists of Sgf11, Sgf73, Sus1 and the deubiquitinating enzyme, Ubp8. The SPT module is shown in purple and the TAF module is shown in blue. The spatial positions of the SAGA proteins in this figure are derived from a model based on data from a recent mass spectrometric study [20].
Figure 2
Figure 2. The structure of the SAGA DUB module
A) The structure of the DUB module bound to ubiquitin aldehyde. The DUB module proteins Ubp8, Sgf11, Sus1 and Sgf73 (colors indicated in figure, zinc atoms are colored dark pink) form a highly intertwined complex. The four proteins are organized around the two globular domains of Ubp8 forming the ZnF-UBP/assembly lobe, and the USP/catalytic lobe. Ubiquitin aldehyde (yellow) is bound to the ubiquitin-binding pocket with its C-terminal tail extending into the Ubp8 active site. B) View of the DUB module, rotated 180°. Two novel USP zinc-binding sites (blue circles) are conserved in the human and Drosophila homologues of Ubp8. A green arrow points in the direction of SAGA, indicating the region where the DUBm may be anchored to the rest of SAGA, and the Ubp8 active site is indicated. C) The USP domain of Ubp8, indicating the thumb, palm and fingers regions. The globular portion of ubiquitin (yellow) binds to the fingers region. D) While Ubp8 contains globular domains, the other three proteins are mostly non-globular and adopt conformations that depend on their incorporation into the complex.
Figure 3
Figure 3. The activation of Ubp8 and substrate recognition of the DUBm
A) The Sgf11 zinc finger binds adjacent to the Ubp8 active site and interacts with loops L2 and L3, which contain the predicted oxyanion hole residues N141, D444, and the catalytic residues, N443 and C146. Also shown is H427, the third residue in the catalytic triad. The active site residues adopt the same conformation in the absence (purple DUBm) and presence (grey DUBm) of ubiquitin (colors indicated in figure, zinc atoms are colored dark pink). B) Conserved arginine residues that form a basic patch on the Sgf11 zinc finger are indicated, including Arg98 and Arg99, which are disordered in the structure and have been modeled into the figure (indicated by the dashed line). C) The fingers region of Ubp8 adopts an open conformation in the presence (gray) and absence (magenta) of bound ubiquitin. By contrast, fingers region in the structure of human USP8 [36] occludes the ubiquitin-binding pocket, and must undergo a conformational change in order to bind ubiquitin, as indicated by the black arrow.
Figure 4
Figure 4. Sus1 plays a conserved role in the SAGA DUB module and in the TREX-2 complex
As in the DUB module (left), Sus1 also forms an alpha-helical clamp in the TREX-2 complex (right), which contains two copies of Sus1 and one copy of Cdc31 bound to the extended N-terminal helix of Sac3.
Figure 5
Figure 5. The SCA7 domain of ATNX7 and the Tudor domain of Sgf29
A) The SCA7 zinc finger of ATXN7 Also shown is the zinc coordinated by a histidine and three cysteines. B) The ATXN7L3 SCA7 zinc finger. Its zinc binding site is similar to that of ATXN7-SCA7. C) Structure of the Tudor domains of Sgf29 bound to a tri-methylated H3K4 peptide. An arrow indicates the tri-methyl group on Lys4, which lies in a hydrophobic pocket formed by Tyr245, Tyr238, and Phe264, and is further stabilized by interactions with Asp266. Tyr245 and Aps196 also form hydrogen bonds with amide groups on the peptide.
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