Unique protein interaction networks define the chromatin remodelling module of the NuRD complex
Mehdi Sharifi Tabara b c d e, Caroline Giardinab e, Yue Fengb e, Habib Francisb e, Hakimeh Moghaddas Sanif g h, Jason K. K. Lowf g h, Joel P. Mackayf g h, Charles G. Baileya b c d e i j, John E.J. Raskoa b c d e k l✉
- aFaculty of Medicine & Health, The University of Sydney, Sydney, NSW, 2006, Australia
- bGene and Stem Cell Therapy Program Centenary Institute, The University of Sydney, Camperdown, NSW, 2050, Australia
- cFaculty of Medicine &
- dHealth The University of Sydney NSW Australia
- eGene and Stem Cell Therapy Program Centenary Institute, The University of Sydney, Camperdown, NSW, Australia
- fSchool of Life & Environmental Sciences, The University of Sydney, Sydney, NSW, 2006, Australia
- gSchool of Life &
- hEnvironmental Sciences The University of Sydney NSW Australia
- iCancer and Gene Regulation Laboratory Centenary Institute, The University of Sydney, Camperdown, NSW, 2050, Australia
- jCancer & Gene Regulation Laboratory Centenary Institute, The University of Sydney, Camperdown, NSW, Australia
- kCell and Molecular Therapies, Royal Prince Alfred Hospital, Camperdown, NSW, 2050, Australia
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Abstract
The combination of four proteins and their paralogues including MBD2/3, GATAD2A/B, CDK2AP1 and CHD3/4/5, which we refer to as the MGCC module, form the chromatin remodelling module of the nucleosome remodelling and deacetylase (NuRD) complex. To date, mechanisms by which the MGCC module acquires paralogue-specific function and specificity have not been addressed. Understanding the protein-protein interaction (PPI) network of the MGCC subunits is essential for defining underlying mechanisms of gene regulation. Therefore, using pulldown followed by mass spectrometry analysis (PD-MS), we report a proteome-wide interaction network of the MGCC module in a paralogue-specific manner. Our data also demonstrate that the disordered C-terminal region of CHD3/4/5 is a gateway to incorporate remodelling activity into both ChAHP (CHD4, ADNP, HP1γ) and NuRD complexes in a mutually exclusive manner. We define a short aggregation-prone region (APR) within the C-terminal segment of GATAD2B that is essential for the interaction of CHD4 and CDK2AP1 with the NuRD complex. Finally, we also report an association of CDK2AP1 with the nuclear receptor co-repressor (NCOR) complex. Overall, this study provides insight into the possible mechanisms through which the MGCC module can achieve specificity and diverse biological functions.