5DAH

Crystal structure of PZP domain of human AF10 protein fused with Histone H3 peptide

Summary for 5DAH

• Entry DOI: 10.2210/pdb5dah/pdb
• Related: 5DAG
• Descriptor: Protein AF-10, Histone H3 peptide, ZINC ION, ... (5 entities in total)
• Functional Keywords: phd finger, histone tail reader, epigenetics, h3k27 recognition, peptide binding protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 49277.41

Authors

Chen, S.,Patel, D.J. (deposition date: 2015-08-19, release date: 2015-10-21, Last modification date: 2024-03-06)

Primary citation

Chen, S.,Yang, Z.,Wilkinson, A.W.,Deshpande, A.J.,Sidoli, S.,Krajewski, K.,Strahl, B.D.,Garcia, B.A.,Armstrong, S.A.,Patel, D.J.,Gozani, O.
The PZP Domain of AF10 Senses Unmodified H3K27 to Regulate DOT1L-Mediated Methylation of H3K79.
Mol.Cell, 60:319-327, 2015

PubMed Abstract: AF10, a DOT1L cofactor, is required for H3K79 methylation and cooperates with DOT1L in leukemogenesis. However, the molecular mechanism by which AF10 regulates DOT1L-mediated H3K79 methylation is not clear. Here we report that AF10 contains a "reader" domain that couples unmodified H3K27 recognition to H3K79 methylation. An AF10 region consisting of a PHD finger-Zn knuckle-PHD finger (PZP) folds into a single module that recognizes amino acids 22-27 of H3, and this interaction is abrogated by H3K27 modification. Structural studies reveal that H3 binding triggers rearrangement of the PZP module to form an H3(22-27)-accommodating channel and that the unmodified H3K27 side chain is encased in a compact hydrogen-bond acceptor-lined cage. In cells, PZP recognition of H3 is required for H3K79 dimethylation, expression of DOT1L-target genes, and proliferation of DOT1L-addicted leukemic cells. Together, our results uncover a pivotal role for H3K27-via readout by the AF10 PZP domain-in regulating the cancer-associated enzyme DOT1L.

PubMed: 26439302
DOI: 10.1016/j.molcel.2015.08.019

Experimental method

X-RAY DIFFRACTION (2.611 Å)