PDBsum entry 4n4h

Transcription

PDB id: 4n4h

Contents

Protein chains

188 a.a.

11 a.a.

Ligands

PO4

PEG

Metals

_ZN

Waters ×55

PDB id:

4n4h

Name:

Transcription

Title:

Crystal structure of the bromo-pwwp of the mouse zinc finger mynd-type containing 11 isoform alpha in complex with histone h3.1k36me3

Structure:

Zinc finger mynd domain-containing protein 11. Chain: a. Fragment: unp residues 154-371. Engineered: yes. Mutation: yes. Peptide from histone h3.1. Chain: b. Engineered: yes

Source:

Mus musculus. Mouse. Organism_taxid: 10090. Gene: zmynd11. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Homo sapiens. Human.

Resolution:

2.30Å R-factor: 0.211 R-free: 0.263

Authors:

Y.Li,Y.Ren,H.Li

Key ref:

H.Wen et al. (2014). ZMYND11 links histone H3.3K36me3 to transcription elongation and tumour suppression. Nature, 508, 263-268. PubMed id: 24590075 DOI: 10.1038/nature13045

Date:

08-Oct-13 Release date: 05-Mar-14

Protein chain

Q8R5C8  (ZMY11_MOUSE) -  Zinc finger MYND domain-containing protein 11 from Mus musculus

Seq: 602 a.a.

Struc: 188 a.a.*

Protein chain

P68431  (H31_HUMAN) -  Histone H3.1 from Homo sapiens

Seq: 136 a.a.

Struc: 11 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

DOI no: 10.1038/nature13045

Nature 508:263-268 (2014)

PubMed id: 24590075

ZMYND11 links histone H3.3K36me3 to transcription elongation and tumour suppression.

H.Wen, Y.Li, Y.Xi, S.Jiang, S.Stratton, D.Peng, K.Tanaka, Y.Ren, Z.Xia, J.Wu, B.Li, M.C.Barton, W.Li, H.Li, X.Shi.

ABSTRACT

Recognition of modified histones by 'reader' proteins plays a critical role in the regulation of chromatin. H3K36 trimethylation (H3K36me3) is deposited onto the nucleosomes in the transcribed regions after RNA polymerase II elongation. In yeast, this mark in turn recruits epigenetic regulators to reset the chromatin to a relatively repressive state, thus suppressing cryptic transcription. However, much less is known about the role of H3K36me3 in transcription regulation in mammals. This is further complicated by the transcription-coupled incorporation of the histone variant H3.3 in gene bodies. Here we show that the candidate tumour suppressor ZMYND11 specifically recognizes H3K36me3 on H3.3 (H3.3K36me3) and regulates RNA polymerase II elongation. Structural studies show that in addition to the trimethyl-lysine binding by an aromatic cage within the PWWP domain, the H3.3-dependent recognition is mediated by the encapsulation of the H3.3-specific 'Ser 31' residue in a composite pocket formed by the tandem bromo-PWWP domains of ZMYND11. Chromatin immunoprecipitation followed by sequencing shows a genome-wide co-localization of ZMYND11 with H3K36me3 and H3.3 in gene bodies, and its occupancy requires the pre-deposition of H3.3K36me3. Although ZMYND11 is associated with highly expressed genes, it functions as an unconventional transcription co-repressor by modulating RNA polymerase II at the elongation stage. ZMYND11 is critical for the repression of a transcriptional program that is essential for tumour cell growth; low expression levels of ZMYND11 in breast cancer patients correlate with worse prognosis. Consistently, overexpression of ZMYND11 suppresses cancer cell growth in vitro and tumour formation in mice. Together, this study identifies ZMYND11 as an H3.3-specific reader of H3K36me3 that links the histone-variant-mediated transcription elongation control to tumour suppression.