DAXX envelops a histone H3.3-H4 dimer for H3.3-specific recognition.
Histone chaperones represent a structurally and functionally diverse family of histone-binding proteins that prevent promiscuous interactions of histones before their assembly into chromatin. DAXX is a metazoan histone chaperone specific to the evolutionarily conserved histone variant H3.3. Here we report the crystal structures of the DAXX histone-binding domain with a histone H3.3-H4 dimer, including mutants within DAXX and H3.3, together with in vitro and in vivo functional studies that elucidate the principles underlying H3.3 recognition specificity. Occupying 40% of the histone surface-accessible area, DAXX wraps around the H3.3-H4 dimer, with complex formation accompanied by structural transitions in the H3.3-H4 histone fold. DAXX uses an extended α-helical conformation to compete with major inter-histone, DNA and ASF1 interaction sites. Our structural studies identify recognition elements that read out H3.3-specific residues, and functional studies address the contributions of Gly 90 in H3.3 and Glu 225 in DAXX to chaperone-mediated H3.3 variant recognition specificity.
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, New York 10065, USA.
Simon J
SJ
Elsässer
Hongda
H
Huang
Peter W
PW
Lewis
Jason W
JW
Chin
C David
CD
Allis
Dinshaw J
DJ
Patel
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D001667:Binding, Competitive; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D056970:Co-Repressor Proteins; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D056488:Histone Chaperones / Q000737:chemistry / Q000378:metabolism; D006657:Histones / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D009707:Nucleosomes / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D055503:Protein Multimerization; D013379:Substrate Specificity; D014867:Water / Q000737:chemistry / Q000378:metabolism
C491641:ASF1A protein, human; C491640:ASF1B protein, human; D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D056488:Histone Chaperones; D006657:Histones; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D009707:Nucleosomes; D014867:Water; D004247:DNA