title: Recognition of modification status on a histone H3 tail by linked histone reader modules of the epigenetic regulator UHRF1.
abstract: Multiple covalent modifications on a histone tail are often recognized by linked histone reader modules. UHRF1 [ubiquitin-like, containing plant homeodomain (PHD) and really interesting new gene (RING) finger domains 1], an essential factor for maintenance of DNA methylation, contains linked two-histone reader modules, a tandem Tudor domain and a PHD finger, tethered by a 17-aa linker, and has been implicated to link histone modifications and DNA methylation. Here, we present the crystal structure of the linked histone reader modules of UHRF1 in complex with the amino-terminal tail of histone H3. Our structural and biochemical data provide the basis for combinatorial readout of unmodified Arg-2 (H3-R2) and methylated Lys-9 (H3-K9) by the tandem tudor domain and the PHD finger. The structure reveals that the intermodule linker plays an essential role in the formation of a histone H3-binding hole between the reader modules by making extended contacts with the tandem tudor domain. The histone H3 tail fits into the hole by adopting a compact fold harboring a central helix, which allows both of the reader modules to simultaneously recognize the modification states at H3-R2 and H3-K9. Our data also suggest that phosphorylation of a linker residue can modulate the relative position of the reader modules, thereby altering the histone H3-binding mode. This finding implies that the linker region plays a role as a functional switch of UHRF1 involved in multiple regulatory pathways such as maintenance of DNA methylation and transcriptional repression.
authors: Department of Molecular Engineering, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan.
authors: Kyohei
authors: K
authors: Arita
authors: Shin
authors: S
authors: Isogai
authors: Takashi
authors: T
authors: Oda
authors: Motoko
authors: M
authors: Unoki
authors: Kazuya
authors: K
authors: Sugita
authors: Naotaka
authors: N
authors: Sekiyama
authors: Keiko
authors: K
authors: Kuwata
authors: Ryuji
authors: R
authors: Hamamoto
authors: Hidehito
authors: H
authors: Tochio
authors: Mamoru
authors: M
authors: Sato
authors: Mariko
authors: M
authors: Ariyoshi
authors: Masahiro
authors: M
authors: Shirakawa
mesh_terms: D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002846:Chromatography, Affinity; D002850:Chromatography, Gel; D002852:Chromatography, Ion Exchange; D002853:Chromatography, Liquid; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D024202:Electrophoretic Mobility Shift Assay; D004926:Escherichia coli; D006657:Histones / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism*; D053719:Tandem Mass Spectrometry; D044767:Ubiquitin-Protein Ligases
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D006657:Histones; D046912:Multiprotein Complexes; D021122:Protein Subunits; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases