PDBsum entry 2qic

Antitumor protein, apoptosis

PDB id: 2qic

Contents

Protein chain

51 a.a. *

Ligands

ALA-ARG-THR-M3L-GLN-THR-ALA-ARG

Metals

_ZN ×2

Waters ×41

* Residue conservation analysis

PDB id:

2qic

Name:

Antitumor protein, apoptosis

Title:

Crystal structure of the ing1 phd finger in complex with a histone h3k4me3 peptide

Structure:

Inhibitor of growth protein 1. Chain: a. Fragment: phd domain (residues 345-404). Engineered: yes. H3k4me3 peptide. Chain: b. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ing1. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: synthetic peptide h3k4me3

Resolution:

2.10Å R-factor: 0.240 R-free: 0.264

Authors:

P.V.Pena,K.Champagne,R.Zhao,T.G.Kutateladze

Key ref:

P.V.Peña et al. (2008). Histone H3K4me3 binding is required for the DNA repair and apoptotic activities of ING1 tumor suppressor. J Mol Biol, 380, 303-312. PubMed id: 18533182 DOI: 10.1016/j.jmb.2008.04.061

Date:

03-Jul-07 Release date: 13-May-08

Protein chain

Q9UK53  (ING1_HUMAN) -  Inhibitor of growth protein 1 from Homo sapiens

Seq: 422 a.a.

Struc: 51 a.a.

DOI no: 10.1016/j.jmb.2008.04.061

J Mol Biol 380:303-312 (2008)

PubMed id: 18533182

Histone H3K4me3 binding is required for the DNA repair and apoptotic activities of ING1 tumor suppressor.

P.V.Peña, R.A.Hom, T.Hung, H.Lin, A.J.Kuo, R.P.Wong, O.M.Subach, K.S.Champagne, R.Zhao, V.V.Verkhusha, G.Li, O.Gozani, T.G.Kutateladze.

ABSTRACT

Inhibitor of growth 1 (ING1) is implicated in oncogenesis, DNA damage repair, and apoptosis. Mutations within the ING1 gene and altered expression levels of ING1 are found in multiple human cancers. Here, we show that both DNA repair and apoptotic activities of ING1 require the interaction of the C-terminal plant homeodomain (PHD) finger with histone H3 trimethylated at Lys4 (H3K4me3). The ING1 PHD finger recognizes methylated H3K4 but not other histone modifications as revealed by the peptide microarrays. The molecular mechanism of the histone recognition is elucidated based on a 2.1 A-resolution crystal structure of the PHD-H3K4me3 complex. The K4me3 occupies a deep hydrophobic pocket formed by the conserved Y212 and W235 residues that make cation-pi contacts with the trimethylammonium group. Both aromatic residues are essential in the H3K4me3 recognition, as substitution of these residues with Ala disrupts the interaction. Unlike the wild-type ING1, the W235A mutant, overexpressed in the stable clones of melanoma cells or in HT1080 cells, was unable to stimulate DNA repair after UV irradiation or promote DNA-damage-induced apoptosis, indicating that H3K4me3 binding is necessary for these biological functions of ING1. Furthermore, N216S, V218I, and G221V mutations, found in human malignancies, impair the ability of ING1 to associate with H3K4me3 or to induce nucleotide repair and cell death, linking the tumorigenic activity of ING1 with epigenetic regulation. Together, our findings reveal the critical role of the H3K4me3 interaction in mediating cellular responses to genotoxic stresses and offer new insight into the molecular mechanism underlying the tumor suppressive activity of ING1.

Selected figure(s)

Figure 1.
Fig. 1. The ING1 PHD finger recognizes H3K4me3. (a) Peptide microarrays containing the indicated histone peptides were probed with GST–ING1 PHD. Red spots indicate binding. me, methylation; ac, acetylation; ph, phosphorylation; s, symmetric; a, asymmetric. (b) Structure of the ING1 PHD finger in complex with the histone H3K4me3 peptide. The PHD finger is shown as solid surface. The histone peptide is depicted as ball-and-stick model with C, O, and N atoms colored green, red, and blue, respectively. (c) The PHD finger is shown as a ribbon with residues mutated in human cancers colored brown. (d) Interactions of the GST-fusion wild-type and mutant ING1 PHD fingers with biotinylated histone peptides examined by Western blot experiments.

Figure 6.
Fig. 6. A model of the ING1 functioning. Binding of the C-terminal PHD finger and the N-terminal SAID domain of ING1 to H3K4me3 and a SAP30 subunit of the Sin3a/HDAC1/2, respectively, tethers the histone modifying complex to the nucleosome for subsequent deacetylation of acetylated lysine residues of histone H3.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2008, 380, 303-312) copyright 2008.

Figures were selected by an automated process.