Hoffmeister, Helen and Fuchs, Andreas and Komives, Elizabeth and Groebner-Ferreira, Regina and Strobl, Laura and Nazet, Julian and Heizinger, Leonhard and Merkl, Rainer and Dove, Stefan and Laengst, Gernot (2021) Sequence and functional differences in the ATPase domains of CHD3 and SNF2H promise potential for selective regulability and drugability. FEBS JOURNAL, 288 (13). pp. 4000-4023. ISSN 1742-464X, 1742-4658
Full text not available from this repository. (Request a copy)Abstract
Chromatin remodelers use the energy of ATP hydrolysis to regulate chromatin dynamics. Their impact for development and disease requires strict enzymatic control. Here, we address the differential regulability of the ATPase domain of hSNF2H and hCHD3, exhibiting similar substrate affinities and enzymatic activities. Both enzymes are comparably strongly inhibited in their ATP hydrolysis activity by the competitive ATPase inhibitor ADP. However, the nucleosome remodeling activity of SNF2H is more strongly affected than that of CHD3. Beside ADP, also IP6 inhibits the nucleosome translocation of both enzymes to varying degrees, following a competitive inhibition mode at CHD3, but not at SNF2H. Our observations are further substantiated by mutating conserved Q- and K-residues of ATPase domain motifs. The variants still bind both substrates and exhibit a wild-type similar, basal ATP hydrolysis. Apart from three CHD3 variants, none of the variants can translocate nucleosomes, suggesting for the first time that the basal ATPase activity of CHD3 is sufficient for nucleosome remodeling. Together with the ADP data, our results propose a more efficient coupling of ATP hydrolysis and remodeling in CHD3. This aspect correlates with findings that CHD3 nucleosome translocation is visible at much lower ATP concentrations than SNF2H. We propose sequence differences between the ATPase domains of both enzymes as an explanation for the functional differences and suggest that aa interactions, including the conserved Q- and K-residues distinctly regulate ATPase-dependent functions of both proteins. Our data emphasize the benefits of remodeler ATPase domains for selective drugability and/or regulability of chromatin dynamics.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CHROMATIN-REMODELING COMPLEXES; INOSITOL HEXAPHOSPHATE; SWI2/SNF2 PROTEIN; DNA-BINDING; Q-MOTIF; RNA; NUCLEOSOMES; HYDROLYSIS; BRG1; IP6; ADP; ATPase; chromatin; competitive inhibitor; remodeling enzyme |
| Subjects: | 500 Science > 570 Life sciences 600 Technology > 615 Pharmacy |
| Divisions: | Biology, Preclinical Medicine > Institut für Biophysik und physikalische Biochemie > Prof. Dr. Rainer Merkl Biology, Preclinical Medicine > Institut für Biochemie, Genetik und Mikrobiologie > Lehrstuhl für Biochemie III > Prof. Dr. Gernot Längst Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 19 Jul 2022 08:45 |
| Last Modified: | 19 Jul 2022 08:45 |
| URI: | https://pred.uni-regensburg.de/id/eprint/45799 |
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