Serine 298 Phosphorylation in Linker 2 of UHRF1 Regulates Ligand-Binding Property of Its Tandem Tudor Domain.

Autor: Kori S; Structure Biology Laboratory, Graduate School of Medical Life Science, Yokohama City University, 1-7-29, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan., Jimenji T; Structure Biology Laboratory, Graduate School of Medical Life Science, Yokohama City University, 1-7-29, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan., Ekimoto T; Computational Life Science Laboratory, Graduate School of Medical Life Science, Yokohama City University, 1-7-29, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan., Sato M; Mitsui Knowledge Industry, 2-5-1 Atago, Minato-ku, Tokyo 105-6215, Japan., Kusano F; Structure Biology Laboratory, Graduate School of Medical Life Science, Yokohama City University, 1-7-29, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan., Oda T; Structure Biology Laboratory, Graduate School of Medical Life Science, Yokohama City University, 1-7-29, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan., Unoki M; Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan., Ikeguchi M; Computational Life Science Laboratory, Graduate School of Medical Life Science, Yokohama City University, 1-7-29, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan; RIKEN Medical Sciences Innovation Hub Program, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan., Arita K; Structure Biology Laboratory, Graduate School of Medical Life Science, Yokohama City University, 1-7-29, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan; JST, PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan. Electronic address: aritak@yokohama-cu.ac.jp.
Jazyk: angličtina
Zdroj: Journal of molecular biology [J Mol Biol] 2020 Jun 26; Vol. 432 (14), pp. 4061-4075. Date of Electronic Publication: 2020 May 16.
DOI: 10.1016/j.jmb.2020.05.006
Abstrakt: Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is an essential factor for the maintenance of mammalian DNA methylation and harbors several reader modules for recognizing epigenetic marks. The tandem Tudor domain (TTD) of UHRF1 has a peptide-binding groove that functions as a binding platform for intra- or intermolecular interactions. Besides the groove interacting with unphosphorylated linker 2 and spacer of UHRF1, it also interacts with di/tri-methylated histone H3 at Lys9 and DNA ligase 1 (LIG1) at Lys126. Here we focus on the phosphorylation of Ser298 in linker 2, which was implied to regulate the ligand-binding property of the TTD. Although the protein expression level of UHRF1 is unchanged throughout the cell cycle, Ser298 phosphorylated form of UHRF1 is notably increased in the G2/M phase, which is revealed by immunoprecipitation followed by Western blotting. Molecularly, while unphosphorylated linker 2 covers the peptide-binding groove to prevent access of other interactors, small-angle X-ray scattering, thermal stability assay and molecular dynamics simulation revealed that the phosphate group of Ser298 dissociates linker 2 from the peptide-binding groove of the TTD to permit the other interactors to access to the groove. Our data reveal a mechanism in which Ser298 phosphorylation in linker 2 triggers a change of the TTD's structure and may affect multiple functions of UHRF1 by facilitating associations with LIG1 at DNA replication sites and histone H3K9me2/me3 at heterochromatic regions.
Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest with the contents of this article.
(Copyright © 2020 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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