3DB3

Crystal structure of the tandem tudor domains of the E3 ubiquitin-protein ligase UHRF1 in complex with trimethylated histone H3-K9 peptide

Summary for 3DB3

• Entry DOI: 10.2210/pdb3db3/pdb
• Related: 2FAZ 3BI7 3CLZ 3DB4
• Descriptor: E3 ubiquitin-protein ligase UHRF1, Trimethylated histone H3-K9 peptide (3 entities in total)
• Functional Keywords: cell cycle, dna damage, dna repair, tandem tudor domains, ligase, metal binding, dna replication, transcriptional silencing, chromatin, phosphorylation, transcription, transcription regulation, ubl conjugation pathway, zinc-finger, structural genomics, structural genomics consortium, sgc, dna-binding, metal-binding, nucleus, phosphoprotein
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: Q96T88 Q71DI3
• Total number of polymer chains: 2
• Total formula weight: 19718.38

Authors

Walker, J.R.,Avvakumov, G.V.,Xue, S.,Dong, A.,Li, Y.,Bountra, C.,Weigelt, J.,Arrowsmith, C.H.,Edwards, A.M.,Bochkarev, A.,Dhe-Paganon, S.,Structural Genomics Consortium (SGC) (deposition date: 2008-05-30, release date: 2008-09-16, Last modification date: 2012-04-18)

Primary citation

Nady, N.,Lemak, A.,Walker, J.R.,Avvakumov, G.V.,Kareta, M.S.,Achour, M.,Xue, S.,Duan, S.,Allali-Hassani, A.,Zuo, X.,Wang, Y.X.,Bronner, C.,Chedin, F.,Arrowsmith, C.H.,Dhe-Paganon, S.
Recognition of multivalent histone states associated with heterochromatin by UHRF1 protein.
J.Biol.Chem., 286:24300-24311, 2011

PubMed Abstract: Histone modifications and DNA methylation represent two layers of heritable epigenetic information that regulate eukaryotic chromatin structure and gene activity. UHRF1 is a unique factor that bridges these two layers; it is required for maintenance DNA methylation at hemimethylated CpG sites, which are specifically recognized through its SRA domain and also interacts with histone H3 trimethylated on lysine 9 (H3K9me3) in an unspecified manner. Here we show that UHRF1 contains a tandem Tudor domain (TTD) that recognizes H3 tail peptides with the heterochromatin-associated modification state of trimethylated lysine 9 and unmodified lysine 4 (H3K4me0/K9me3). Solution NMR and crystallographic data reveal the TTD simultaneously recognizes H3K9me3 through a conserved aromatic cage in the first Tudor subdomain and unmodified H3K4 within a groove between the tandem subdomains. The subdomains undergo a conformational adjustment upon peptide binding, distinct from previously reported mechanisms for dual histone mark recognition. Mutant UHRF1 protein deficient for H3K4me0/K9me3 binding shows altered localization to heterochromatic chromocenters and fails to reduce expression of a target gene, p16(INK4A), when overexpressed. Our results demonstrate a novel recognition mechanism for the combinatorial readout of histone modification states associated with gene silencing and add to the growing evidence for coordination of, and cross-talk between, the modification states of H3K4 and H3K9 in regulation of gene expression.

PubMed: 21489993
DOI: 10.1074/jbc.M111.234104

Experimental method

X-RAY DIFFRACTION (2.4 Å)