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PDBsum entry 2wp1
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Transcription/peptide
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PDB id
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2wp1
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References listed in PDB file
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Key reference
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Title
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Cooperative binding of two acetylation marks on a histone tail by a single bromodomain.
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Authors
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J.Morinière,
S.Rousseaux,
U.Steuerwald,
M.Soler-López,
S.Curtet,
A.L.Vitte,
J.Govin,
J.Gaucher,
K.Sadoul,
D.J.Hart,
J.Krijgsveld,
S.Khochbin,
C.W.Müller,
C.Petosa.
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Ref.
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Nature, 2009,
461,
664-668.
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PubMed id
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Abstract
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A key step in many chromatin-related processes is the recognition of histone
post-translational modifications by effector modules such as bromodomains and
chromo-like domains of the Royal family. Whereas effector-mediated recognition
of single post-translational modifications is well characterized, how the cell
achieves combinatorial readout of histones bearing multiple modifications is
poorly understood. One mechanism involves multivalent binding by linked effector
modules. For example, the tandem bromodomains of human TATA-binding
protein-associated factor-1 (TAF1) bind better to a diacetylated histone H4 tail
than to monoacetylated tails, a cooperative effect attributed to each
bromodomain engaging one acetyl-lysine mark. Here we report a distinct mechanism
of combinatorial readout for the mouse TAF1 homologue Brdt, a testis-specific
member of the BET protein family. Brdt associates with hyperacetylated histone
H4 (ref. 7) and is implicated in the marked chromatin remodelling that follows
histone hyperacetylation during spermiogenesis, the stage of spermatogenesis in
which post-meiotic germ cells mature into fully differentiated sperm. Notably,
we find that a single bromodomain (BD1) of Brdt is responsible for selectively
recognizing histone H4 tails bearing two or more acetylation marks. The crystal
structure of BD1 bound to a diacetylated H4 tail shows how two acetyl-lysine
residues cooperate to interact with one binding pocket. Structure-based
mutagenesis that reduces the selectivity of BD1 towards diacetylated tails
destabilizes the association of Brdt with acetylated chromatin in vivo.
Structural analysis suggests that other chromatin-associated proteins may be
capable of a similar mode of ligand recognition, including yeast Bdf1, human
TAF1 and human CBP/p300 (also known as CREBBP and EP300, respectively). Our
findings describe a new mechanism for the combinatorial readout of histone
modifications in which a single effector module engages two marks on a histone
tail as a composite binding epitope.
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