Abstract
Chromatin remodeling plays important roles in gene regulation during development, differentiation and in disease. The chromatin remodeling enzyme CHD4 is a component of the NuRD and ChAHP complexes that are involved in gene repression. Here, we report the cryo-electron microscopy (cryo-EM) structure of Homo sapiens CHD4 engaged with a nucleosome core particle in the presence of the non-hydrolysable ATP analogue AMP-PNP at an overall resolution of 3.1 Å. The ATPase motor of CHD4 binds and distorts nucleosomal DNA at superhelical location (SHL) +2, supporting the 'twist defect' model of chromatin remodeling. CHD4 does not induce unwrapping of terminal DNA, in contrast to its homologue Chd1, which functions in gene activation. Our structure also maps CHD4 mutations that are associated with human cancer or the intellectual disability disorder Sifrim-Hitz-Weiss syndrome.
Highlights
Chromatin remodelling plays important roles in gene regulation during development, differentiation and in disease
To investigate how the human chromatin remodeller CHD4 engages a nucleosome, we determined the structure of H. sapiens CHD4 bound to a Xenopus laevis nucleosome core particle in the presence of the ATP analogue
To determine the structure of the nucleosome-CHD4 complex, we collected single particle cryo-electron microscopy (cryo-EM) data on a Titan Krios (FEI) microscope equipped with a K2 direct electron detector (Gatan) (Methods)
Summary
Chromatin remodelling plays important roles in gene regulation during development, differentiation and in disease. Maintenance of the appropriate chromatin state requires ATP-dependent chromatin-remodelling enzymes. These ‘chromatin remodellers’ are divided into four families called CHD, SWI/SNF, ISWI, and INO80 (Clapier et al, 2017). All chromatin remodellers contain a conserved ATPase core that hydrolyses ATP to alter contacts between nucleosomal DNA and the histone octamer and to facilitate nucleosome assembly, sliding, ejection, or histone exchange. Members of the CHD (‘chromodomain helicase DNA-binding’) family of chromatin remodellers all contain a central SNF2-like ATPase motor domain and a double chromodomain in their N-terminal region. The double chromodomain binds modified histones (Sims et al, 2005) and interacts with nucleosomal DNA to regulate ATPase activity (Nodelman et al, 2017). The resolution of these studies was limited, such that atomic details were not resolved
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