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

被引:72
作者
Chignola, Francesca [2 ]
Gaetani, Massimiliano [2 ]
Rebane, Ana [1 ]
Org, Tonis [1 ]
Mollica, Luca [2 ]
Zucchelli, Chiara [2 ]
Spitaleri, Andrea [2 ]
Mannella, Valeria [2 ]
Peterson, Paert [1 ]
Musco, Giovanna [2 ]
机构
[1] Univ Tartu, Dept Mol Pathol, EE-50411 Tartu, Estonia
[2] Ist Sci San Raffaele, Biomol NMR Lab, Dulbecco Telethon Inst, I-20132 Milan, Italy
关键词
LYSINE-4; TRIMETHYLATION; ARGININE METHYLATION; H3K4ME3; RECOGNITION; PLANT HOMEODOMAIN; NMR-SPECTROSCOPY; MOLECULAR-BASIS; AIRE; PROTEIN; BINDING; GENE;
D O I
10.1093/nar/gkp166
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:2951 / 2961
页数:11
相关论文
共 57 条
[1]   THE PHD FINGER - IMPLICATIONS FOR CHROMATIN-MEDIATED TRANSCRIPTIONAL REGULATION [J].
AASLAND, R ;
GIBSON, TJ ;
STEWART, AF .
TRENDS IN BIOCHEMICAL SCIENCES, 1995, 20 (02) :56-59
[2]   Projection of an immunological self shadow within the thymus by the aire protein [J].
Anderson, MS ;
Venanzi, ES ;
Klein, L ;
Chen, ZB ;
Berzins, SP ;
Turley, SJ ;
von Boehmer, H ;
Bronson, R ;
Dierich, A ;
Benoist, C ;
Mathis, D .
SCIENCE, 2002, 298 (5597) :1395-1401
[3]   PHD fingers in human diseases: Disorders arising from misinterpreting epigenetic marks [J].
Baker, Lindsey A. ;
Allis, C. David ;
Wang, Gang G. .
MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS, 2008, 647 (1-2) :3-12
[4]   The PHD finger, a nuclear protein-interaction domain [J].
Bienz, M .
TRENDS IN BIOCHEMICAL SCIENCES, 2006, 31 (01) :35-40
[5]   Mutations in the AIRE gene:: Effects on subcellular location and transactivation function of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protein [J].
Björses, P ;
Halonen, M ;
Palvimo, JJ ;
Kolmer, M ;
Aaltonen, J ;
Ellonen, P ;
Perheentupa, J ;
Ulmanen, I ;
Peltonen, L .
AMERICAN JOURNAL OF HUMAN GENETICS, 2000, 66 (02) :378-392
[6]   NMR structure of the first PHD finger of autoimmune regulator protein (AIRE1) [J].
Bottomley, MJ ;
Stier, G ;
Pennacchini, D ;
Legube, G ;
Simon, B ;
Akhtar, A ;
Sattler, M ;
Musco, G .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (12) :11505-11512
[7]   Crystallography & NMR system:: A new software suite for macromolecular structure determination [J].
Brunger, AT ;
Adams, PD ;
Clore, GM ;
DeLano, WL ;
Gros, P ;
Grosse-Kunstleve, RW ;
Jiang, JS ;
Kuszewski, J ;
Nilges, M ;
Pannu, NS ;
Read, RJ ;
Rice, LM ;
Simonson, T ;
Warren, GL .
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1998, 54 :905-921
[8]   Protein backbone angle restraints from searching a database for chemical shift and sequence homology [J].
Cornilescu, G ;
Delaglio, F ;
Bax, A .
JOURNAL OF BIOMOLECULAR NMR, 1999, 13 (03) :289-302
[9]   NMRPIPE - A MULTIDIMENSIONAL SPECTRAL PROCESSING SYSTEM BASED ON UNIX PIPES [J].
DELAGLIO, F ;
GRZESIEK, S ;
VUISTER, GW ;
ZHU, G ;
PFEIFER, J ;
BAX, A .
JOURNAL OF BIOMOLECULAR NMR, 1995, 6 (03) :277-293
[10]   Decoding of methylated histone H3 tail by the Pygo-BCL9 Wnt signaling complex [J].
Fiedler, Marc ;
Sanchez-Barrena, Maria Jose ;
Nekrasov, Maxim ;
Mieszczanek, Juliusz ;
Rybin, Vladimir ;
Mueller, Juerg ;
Evans, Phil ;
Bienz, Mariann .
MOLECULAR CELL, 2008, 30 (04) :507-518