Biochemical and dynamic basis for combinatorial recognition of H3R2K9me2 by dual domains of UHRF1

Abhishek, Suman and Nivya, M Angel and Nakarakanti, Naveen Kumar and Deeksha, Waghela and Khosla, Sanjeev and Eerappa, Rajakumara (2018) Biochemical and dynamic basis for combinatorial recognition of H3R2K9me2 by dual domains of UHRF1. Biochimie. ISSN 0300-9084 (In Press)

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UHRF1 is a multi-domain protein comprising of a tandem tudor (UHRF1 TTD), a PHD finger, and a SET and RING-associated domain. It is required for the maintenance of CG methylation, heterochromatin formation and DNA repair. Isothermal titration calorimetry binding studies of unmodified and methylated lysine histone peptides establish that the UHRF1 TTD binds dimethylated Lys9 on histone H3 (H3K9me2). Further, MD simulation and binding studies reveal that TTD-PHD of UHRF1 (UHRF1 TTD-PHD) preferentially recognizes dimethyl-lysine status. Importantly, we show that Asp145 in the binding pocket determines the preferential recognition of the dimethyl-ammonium group of H3K9me2. Interestingly, PHD finger of the UHRF1 TTD-PHD has a negligible contribution to the binding affinity for recognition of K9me2 by the UHRF1 TTD. Surprisingly, Lys4 methylation on H3 peptide has an insignificant effect on combinatorial recognition of R2 and K9me2 on H3 by the UHRF1 TTD-PHD. We propose that subtle variations of key residues at the binding pocket determine status specific recognition of histone methyl-lysines by the reader domains.

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IITH Creators:
IITH CreatorsORCiD
Eerappa, Rajakumara
Item Type: Article
Uncontrolled Keywords: UHRF1; Tandem Tudor Domains; TTD-PHD; H3K9me2 recognition; 53BP1; Isothermal Titration Calorimetry; Molecular Dynamics Simulation
Subjects: Others > Biotechnology
Divisions: Department of Biotechnology
Depositing User: Team Library
Date Deposited: 18 Apr 2018 04:44
Last Modified: 20 Dec 2018 10:20
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