TY - JOUR
T1 - The role of auxiliary domains in modulating CHD4 activity suggests mechanistic commonality between enzyme families
AU - Zhong, Yichen
AU - Moghaddas Sani, Hakimeh
AU - Paudel, Bishnu P.
AU - Low, Jason K.K.
AU - Silva, Ana P.G.
AU - Mueller, Stefan
AU - Deshpande, Chandrika
AU - Panjikar, Santosh
AU - Reid, Xavier J.
AU - Bedward, Max J.
AU - van Oijen, Antoine M.
AU - Mackay, Joel P.
N1 - Funding Information:
This work was funded by a National Health and Medical Research Council grant to JPM and AMvO (APP1126357). This research was undertaken in part using the MX2 beamline at the Australian Synchrotron, part of ANSTO, and made use of the Australian Cancer Research Foundation (ACRF) detector. We acknowledge the Sydney Mass Spectrometry Core Research Facility at the University of Sydney for providing access to mass spectrometers and thank the technical staff for the maintenance of the instruments.
Funding Information:
This work was funded by a National Health and Medical Research Council grant to JPM and AMvO (APP1126357). This research was undertaken in part using the MX2 beamline at the Australian Synchrotron, part of ANSTO, and made use of the Australian Cancer Research Foundation (ACRF) detector. We acknowledge the Sydney Mass Spectrometry Core Research Facility at the University of Sydney for providing access to mass spectrometers and thank the technical staff for the maintenance of the instruments.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85143508092&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-35002-0
DO - 10.1038/s41467-022-35002-0
M3 - Article
C2 - 36473839
AN - SCOPUS:85143508092
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 7524
ER -