PDBsum entry 2ke1

Gene regulation

PDB id: 2ke1

Contents

Protein chain

66 a.a.

Ligands

ALA-ARG-THR-LYS-GLN-THR-ALA-ARG-LYS-SER

Metals

_ZN ×2

References listed in PDB file

Key reference

• Title: The solution structure of the first phd finger of autoimmune regulator in complex with non-Modified histone h3 tail reveals the antagonistic role of h3r2 methylation.
• Authors: F.Chignola, M.Gaetani, A.Rebane, T.Org, L.Mollica, C.Zucchelli, A.Spitaleri, V.Mannella, P.Peterson, G.Musco.
• Ref.: Nucleic Acids Res, 2009, 37, 2951-2961.
• PubMed id: 19293276

Abstract

Plant homeodomain (PHD) fingers are often present in chromatin-binding proteins and have been shown to bind histone H3 N-terminal tails. Mutations in the autoimmune regulator (AIRE) protein, which harbours two PHD fingers, cause a rare monogenic disease, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). AIRE activates the expression of tissue-specific antigens by directly binding through its first PHD finger (AIRE-PHD1) to histone H3 tails non-methylated at K4 (H3K4me0). Here, we present the solution structure of AIRE-PHD1 in complex with H3K4me0 peptide and show that AIRE-PHD1 is a highly specialized non-modified histone H3 tail reader, as post-translational modifications of the first 10 histone H3 residues reduce binding affinity. In particular, H3R2 dimethylation abrogates AIRE-PHD1 binding in vitro and reduces the in vivo activation of AIRE target genes in HEK293 cells. The observed antagonism by R2 methylation on AIRE-PHD1 binding is unique among the H3K4me0 histone readers and represents the first case of epigenetic negative cross-talk between non-methylated H3K4 and methylated H3R2. Collectively, our results point to a very specific histone code responsible for non-modified H3 tail recognition by AIRE-PHD1 and describe at atomic level one crucial step in the molecular mechanism responsible for antigen expression in the thymus.