7C0M

Human cGAS-nucleosome complex

Summary for 7C0M

• Entry DOI: 10.2210/pdb7c0m/pdb
• EMDB information: 30267
• Descriptor: Histone H3.1, Histone H4, Histone H2A type 1-B/E, ... (8 entities in total)
• Functional Keywords: complex, chromatin, ntase, innate immunity, immunity, nucleosome, cgas, dna binding protein, dna binding protein-dna complex, dna binding protein/dna
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 22
• Total formula weight: 492271.24

Authors

Kujirai, T.,Zierhut, C.,Takizawa, Y.,Kim, R.,Negishi, L.,Uruma, N.,Hirai, S.,Funabiki, H.,Kurumizaka, H. (deposition date: 2020-05-01, release date: 2020-09-16, Last modification date: 2024-03-27)

Primary citation

Kujirai, T.,Zierhut, C.,Takizawa, Y.,Kim, R.,Negishi, L.,Uruma, N.,Hirai, S.,Funabiki, H.,Kurumizaka, H.
Structural basis for the inhibition of cGAS by nucleosomes.
Science, 370:455-458, 2020

PubMed Abstract: The cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) senses invasion of pathogenic DNA and stimulates inflammatory signaling, autophagy, and apoptosis. Organization of host DNA into nucleosomes was proposed to limit cGAS autoinduction, but the underlying mechanism was unknown. Here, we report the structural basis for this inhibition. In the cryo-electron microscopy structure of the human cGAS-nucleosome core particle (NCP) complex, two cGAS monomers bridge two NCPs by binding the acidic patch of the histone H2A-H2B dimer and nucleosomal DNA. In this configuration, all three known cGAS DNA binding sites, required for cGAS activation, are repurposed or become inaccessible, and cGAS dimerization, another prerequisite for activation, is inhibited. Mutating key residues linking cGAS and the acidic patch alleviates nucleosomal inhibition. This study establishes a structural framework for why cGAS is silenced on chromatinized self-DNA.

PubMed: 32912999
DOI: 10.1126/science.abd0237

Experimental method

ELECTRON MICROSCOPY (3.9 Å)