2L3R

NMR structure of UHRF1 Tandem Tudor Domains in a complex with Histone H3 peptide

Summary for 2L3R

• Entry DOI: 10.2210/pdb2l3r/pdb
• NMR Information: BMRB: 17200
• Descriptor: E3 ubiquitin-protein ligase UHRF1, Histone H3 (2 entities in total)
• Functional Keywords: tudor domain, heterochromatin, transcriptional repression, structural genomics, structural genomics consortium, sgc, dna binding protein, dna binding protein-gene regulation complex, dna binding protein/gene regulation
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 20174.53

Authors

Nady, N.,Lemak, A.,Fares, C.,Gutmanas, A.,Avvakumov, G.,Xue, S.,Arrowsmith, C.,Structural Genomics Consortium (SGC) (deposition date: 2010-09-21, release date: 2011-04-13, Last modification date: 2020-02-05)

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

SOLUTION NMR