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Human UHRF1, tandem tudor domain, in complex with H3K9 peptide

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PDB Code 3DB3 Target Class Miscellaneous Target UHRF1 Alias FLJ21925, hNP95, ICBP90, MGC138707, Np95, RNF106 Disease Area/Function cancer, chromatin and epigenetics, signalling Date Deposited May 29 2008 Authors Walker JR, Avvakumov G, Xue S, Dong A., Li Y, Bountra C, Wikstrom M, Arrowsmith CH, Edwards AM, Bochkarev A, Dhe-Paganon S. Related Structure 3CLZ, 3DB4, 3FL2

About this structure

Convergence of the ubiquitylation, acetylation, and methylation systems occurs with two human proteins, UHRF1 and UHRF2. This duo is involved in a number of biological roles including transcriptional upregulation, DNA repair, and epigenetic code inheritance, having the ability to simultaneously bind DNA and recruit key nuclear enzymes. Their DNA binding modules recognize not only inverted CAATT boxes upstream of particular genes (topoisomerase IIα and the retinoblastoma protein), but also hemimethylated CpG islands downstream of the replication fork (1). UHRF proteins orchestrate all three major epigenetic enzymes, including histone acetylases (HDAC1), methyl transferases (DNMT1), and E3 ligases (Ring domain), at least in part to maintain and control epigenetic fidelity during cell proliferation and DNA repair.

We have found a previously unrecognized domain in the N-terminal portion of human UHRF1 (residues 126 – 285) and determined its crystal structure. The structure reveals a tandem Tudor domain (TTD) with closest overall similarity to another known structure being the TTD of Fragile X mental retardation protein (PDB entry 2BKD; RMSD of 3.3 Å, over 96 Cα positions). TTDs have two closely associated lobes with variable relative orientations. Individual lobes have a five-stranded β-barrel fold also present in SH3, CPH, Kow, and single-Tudor domains (Dali or Pfam). The two lobes of UHRF1 (referred to here as TTD1 and TTD2), superimpose well with one another (RMSD of 2.5 Å) despite a lack of detectable sequence identity. Members of the protein ‘Royal Family’ including Tudor, chromo, and MBT domains have been shown to specifically bind to methylated histone peptides, and possess a conserved aromatic cage composed of two to four aromatic residues that utilize cation-π interactions to bind to a positively charged methylated lysines and possibly methylated arginines. This crystal structure shows that the TTD of human UHRF1 is capable of binding trimethylated lysine, too. This domain represents an epigenetic mark reader and allows UHRF1 to bind specifically to K9me3 histone H3, a hallmark of heterochromatin.

References

  1. Avvakumov, G. V., Walker, J. R., Xue, S., Li, Y., Duan, S., Bronner, C., Arrowsmith, C. H., and Dhe-Paganon, S. (2008) Structural basis for recognition of hemi-methylated DNA by the SRA domain of human UHRF1, Nature.