2KE1

Molecular Basis of non-modified histone H3 tail Recognition by the First PHD Finger of Autoimmune Regulator

Summary for 2KE1

• Entry DOI: 10.2210/pdb2ke1/pdb
• Related: 1XWH
• NMR Information: BMRB: 16510
• Descriptor: Autoimmune regulator, H3K4me0, ZINC ION (3 entities in total)
• Functional Keywords: aire, phd finger, histone h3, disease mutation, metal-binding, nucleus, transcription, transcription regulation, zinc, zinc-finger, gene regulation
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus: O43918
• Total number of polymer chains: 2
• Total formula weight: 8426.25

Authors

Chignola, F.,Gaetani, M.,Rebane, A.,Org, T.,Mollica, L.,Zucchelli, C.,Spitaleri, A.,Mannella, V.,Peterson, P.,Musco, G. (deposition date: 2009-01-22, release date: 2009-05-26, Last modification date: 2024-05-29)

Primary citation

Chignola, F.,Gaetani, M.,Rebane, A.,Org, T.,Mollica, L.,Zucchelli, C.,Spitaleri, A.,Mannella, V.,Peterson, P.,Musco, G.
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
Nucleic Acids Res., 37:2951-2961, 2009

PubMed 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.

PubMed: 19293276
DOI: 10.1093/nar/gkp166

Experimental method

SOLUTION NMR