Details

Autor(en) / Beteiligte

• Herbst, Dominik A
• Esbin, Meagan N
• Louder, Robert K
• Dugast-Darzacq, Claire
• Dailey, Gina M
• Fang, Qianglin
• Darzacq, Xavier
• Tjian, Robert
• Nogales, Eva

Titel

Structure of the human SAGA coactivator complex

Ist Teil von

• Nature structural & molecular biology, 2021-12, Vol.28 (12), p.989-996

Ort / Verlag

United States

Erscheinungsjahr

2021

Quelle

MEDLINE

Beschreibungen/Notizen

• The SAGA complex is a regulatory hub involved in gene regulation, chromatin modification, DNA damage repair and signaling. While structures of yeast SAGA (ySAGA) have been reported, there are noteworthy functional and compositional differences for this complex in metazoans. Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA) and show how the arrangement of distinct structural elements results in a globally divergent organization from that of yeast, with a different interface tethering the core module to the TRRAP subunit, resulting in a dramatically altered geometry of functional elements and with the integration of a metazoan-specific splicing module. Our hSAGA structure reveals the presence of an inositol hexakisphosphate (InsP ) binding site in TRRAP and an unusual property of its pseudo-(Ψ)PIKK. Finally, we map human disease mutations, thus providing the needed framework for structure-guided drug design of this important therapeutic target for human developmental diseases and cancer.