Nucleic Acids Research Advance Access originally published online on March 17, 2009
Nucleic Acids Research 2009 37(9):2951-2961; doi:10.1093/nar/gkp166
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Nucleic Acids Research, 2009, Vol. 37, No. 9 2951-2961
© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Structural Biology |
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
1Biomolecular NMR Laboratory, Dulbecco Telethon Institute c/o S. Raffaele Scientific Institute, 20132 Milan, Italy and 2Department of Molecular Pathology, University of Tartu, 50411 Tartu, Estonia
*To whom correspondence should be addressed. Tel: +39 2 26 43 48 24; Fax: +39 2 26 43 41 53; Email: musco.giovanna{at}hsr.it Correspondence may also addressed to Pärt Peterson. Tel: +372 73 74 202; Fax: +372 73 74 207; Email: part.peterson{at}ut.ee
Received January 22, 2009. Revised February 27, 2009. Accepted March 2, 2009.
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.