The role of auxiliary domains in modulating CHD4 activity suggests mechanistic commonality between enzyme families

Authors

Yichen Zhong, The University of Sydney
Hakimeh Moghaddas Sani, The University of Sydney
Bishnu P. Paudel, University of Wollongong
Jason K.K. Low, The University of Sydney
Ana P.G. Silva, The University of Sydney
Stefan Mueller, University of Wollongong
Chandrika Deshpande, The University of Sydney
Santosh Panjikar, Australian Synchrotron
Xavier J. Reid, The University of Sydney
Max J. Bedward, The University of Sydney
Antoine M. van Oijen, University of Wollongong
Joel P. Mackay, The University of Sydney

Publication Name

Nature Communications

Abstract

CHD4 is an essential, widely conserved ATP-dependent translocase that is also a broad tumour dependency. In common with other SF2-family chromatin remodelling enzymes, it alters chromatin accessibility by repositioning histone octamers. Besides the helicase and adjacent tandem chromodomains and PHD domains, CHD4 features 1000 residues of N- and C-terminal sequence with unknown structure and function. We demonstrate that these regions regulate CHD4 activity through different mechanisms. An N-terminal intrinsically disordered region (IDR) promotes remodelling integrity in a manner that depends on the composition but not sequence of the IDR. The C-terminal region harbours an auto-inhibitory region that contacts the helicase domain. Auto-inhibition is relieved by a previously unrecognized C-terminal SANT-SLIDE domain split by ~150 residues of disordered sequence, most likely by binding of this domain to substrate DNA. Our data shed light on CHD4 regulation and reveal strong mechanistic commonality between CHD family members, as well as with ISWI-family remodellers.

Open Access Status

This publication may be available as open access

Volume

13

Issue

1

Article Number

7524

Funding Number

APP1126357

Funding Sponsor

National Health and Medical Research Council