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

Area of Science:

• Structural Biology
• Chromatin Biology
• Molecular Mechanisms

Background:

• DNA in eukaryotic nuclei is packaged into nucleosomes, with positioning governed by ATP-dependent chromatin remodelers like the INO80 complex.
• The INO80 complex influences gene expression, DNA repair, and replication through nucleosome sliding and histone exchange, but its structural mechanism remains unknown.

Purpose of the Study:

• To determine the high-resolution cryo-electron microscopy structure of the INO80 complex core bound to a nucleosome.
• To elucidate the molecular mechanisms underlying INO80-mediated nucleosome sliding and histone exchange.

Main Methods:

• Cryo-electron microscopy (cryo-EM) of the INO80 core complex from Chaetomium thermophilum bound to a nucleosome.
• Integration of structural data with existing biochemical data to propose a mechanistic model.

Main Results:

• The INO80 core structure reveals extensive contacts with the nucleosome, cradling one DNA gyre.
• An Rvb1/Rvb2 AAA+ heterohexamer serves as a scaffold and stator, while the Swi2/Snf2 ATPase motor unwraps DNA and disrupts histone-DNA contacts.
• Arp5 and Ies6 act as a counter-grip, with Arp5's grappler domain binding the nucleosome dyad and connecting to entry DNA.

Conclusions:

• A unified mechanism for nucleosome sliding and histone editing by INO80 is proposed, involving a macromolecular ratchet driven by the ATPase motor.
• The motor persistently pumps DNA against the Arp5 grip, leading to translocation steps and potential histone exchange via transient H2A-H2B exposure.