Structural basis for ATP-dependent chromatin remodelling by the INO80 complex.

Abstract

DNA in the eukaryotic nucleus is packaged in the form of nucleosomes, ~147 base pairs of DNA wrapped around a histone protein octamer. The position and histone composition of nucleosomes is governed by ATP dependent chromatin remodelers1–3 such as the 15 subunit INO80 complex4. INO80 regulates gene expression, DNA repair and replication by sliding nucleosomes, exchanging histone H2A.Z with H2A, and positioning +1 and -1 nucleosomes at promoter DNA5–8. A structure and mechanism for these remodeling reactions is lacking. Here we report the cryo-electron microscopy structure at 4.3Å resolution, with parts at 3.7Å, of an evolutionary conserved core INO80 complex from Chaetomium thermophilum bound to a nucleosome. INO80core cradles one entire gyre of the nucleosome through multivalent DNA and histone contacts. A Rvb1/2 AAA+ ATPase hetero-hexamer is an assembly scaffold for the complex and acts as stator for the motor and nucleosome gripping subunits. The Swi2/Snf2 ATPase motor binds to SHL-6, unwraps ~15 base pairs, disrupts the H2A:DNA contacts and is poised to pump entry DNA into the nucleosome. Arp5-Ies6 grip SHL-2/-3 acting as counter grip for the motor on the other side of the H2A/H2B dimer. The Arp5 insertion domain forms a grappler element that binds the nucleosome dyad, connects the Arp5 core and entry DNA over a distance of ~90Å and packs against histone H2A/H2B near the acidic patch. Our structure together with biochemical data8 suggest a unified mechanism for nucleosome sliding and histone editing by INO80. The motor pumps entry DNA across H2A/H2B against Arp5 and the grappler, sliding nucleosomes as a ratchet. Transient exposure of H2A/H2B by the motor and differential recognition of H2A.Z and H2A may regulate histone exchange during translocation.