Structure of H3K36-methylated nucleosome–PWWP complex reveals multivalent cross-gyre binding

• Published in: Nature structural & molecular biology Vol. 27; no. 1; pp. 8 - 13
• Main Authors: Wang, Haibo, Farnung, Lucas, Dienemann, Christian, Cramer, Patrick
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2020; Nature Publishing Group
• Subjects: 101/28; 631/337/100/1701; 631/337/100/2285; 631/535/1258/1259; 82/83; Acetylation; Adaptor Proteins, Signal Transducing - chemistry; Adaptor Proteins, Signal Transducing - metabolism; Amino Acid Sequence; Binding; Biochemistry; Biological Microscopy; Biomedical and Life Sciences; Chromatin; Cryoelectron Microscopy; Deoxyribonucleic acid; DNA; DNA - chemistry; DNA - metabolism; DNA methylation; DNA repair; Electron microscopy; Genetic research; Genomes; Gyres; Histones; Histones - chemistry; Histones - metabolism; Humans; Life Sciences; Membrane Biology; Methylation; Models, Molecular; Molecular structure; Nucleosomes; Nucleosomes - chemistry; Nucleosomes - metabolism; Observations; Peptides; Properties; Protein Binding; Protein Conformation; Protein Domains; Protein Structure; Sequence Alignment; Transcription Factors - chemistry; Transcription Factors - metabolism; Germany
• ISSN: 1545-9993; 1545-9985; 1545-9985
• DOI: 10.1038/s41594-019-0345-4

Recognition of histone-modified nucleosomes by specific reader domains underlies the regulation of chromatin-associated processes. Whereas structural studies revealed how reader domains bind modified histone peptides, it is unclear how reader domains interact with modified nucleosomes. Here, we report the cryo-electron microscopy structure of the PWWP reader domain of human transcriptional coactivator LEDGF in complex with an H3K36-methylated nucleosome at 3.2–Å resolution. The structure reveals multivalent binding of the reader domain to the methylated histone tail and to both gyres of nucleosomal DNA, explaining the known cooperative interactions. The observed cross-gyre binding may contribute to nucleosome integrity during transcription. The structure also explains how human PWWP domain-containing proteins are recruited to H3K36-methylated regions of the genome for transcription, histone acetylation and methylation, and for DNA methylation and repair. The cryo-EM structure of the PWWP reader domain of the transcriptional coactivator LEDGF in complex with an H3K36-methylated nucleosome reveals multivalent binding of the reader domain to the methylated histone tail and to both gyres of nucleosomal DNA.