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PDBsum entry 3emh
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Gene regulation
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PDB id
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3emh
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References listed in PDB file
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Key reference
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Title
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Wdr5 interacts with mixed lineage leukemia (mll) protein via the histone h3-Binding pocket.
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Authors
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J.J.Song,
R.E.Kingston.
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Ref.
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J Biol Chem, 2008,
283,
35258-35264.
[DOI no: ]
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PubMed id
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Abstract
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WDR5 is a component of the mixed lineage leukemia (MLL) complex, which
methylates lysine 4 of histone H3, and was identified as a methylated Lys-4
histone H3-binding protein. Here, we present a crystal structure of WDR5 bound
to an MLL peptide. Surprisingly, we find that WDR5 utilizes the same pocket
shown to bind histone H3 for this MLL interaction. Furthermore, the WDR5-MLL
interaction is disrupted preferentially by mono- and di-methylated Lys-4 histone
H3 over unmodified and tri-methylated Lys-4 histone H3. These data implicate a
delicate interplay between the effector, WDR5, the catalytic subunit, MLL, and
the substrate, histone H3, of the MLL complex. We suggest that the activity of
the MLL complex might be regulated through this interplay.
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Figure 1.
MLL1 interacts with WDR5 through a histone H3-like motif. A,
a series of deletion mutants of MLL1 was generated and tested
for binding ability to WDR5 by gel filtration chromatography.
MLL205 is the minimal construct that interacts with WDR5. B, the
sequence in MLL1 required for WDR5 interaction contains a
histone H3-like motif and is modestly conserved among MLLs. C,
the histone H3-like motif in MLL1 was tested for binding to
WDR5. The histone H3-like motif in MLL1 is sufficient to
interact with WDR5. D, the histone H3-like motifs in MLL1, MLL2,
MLL3, and MLL4 were tested for binding to WDR5 with GST
pull-down experiments. Only MLL1 and MLL4 are able to bind WDR5.
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Figure 2.
Crystal structure of WDR5 bound to MLL1 peptide. A, top and
side views of WDR5 bound to MLL1 peptide. The MLL1 peptide is
bound to a pocket located at the center of WD40 β-propeller
structure, previously shown to be a histone H3-binding pocket.
B, F[o]-F[c] map (shown in 3σ) between a refined free WDR5 and
data collected from the WDR5-MLLpeptide complex. C,
superimposition between WDR5-MLL peptide (blue-green) and
WDR5-H3 (yellow-red) complex structures. D, the electrostatic
surface potential representations of WDR5-MLL1pep and
WDR5-H3K4me2 complex structures. MLL1 peptide and H3K4me2
peptide utilize distinct pockets for binding.
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The above figures are
reprinted
from an Open Access publication published by the ASBMB:
J Biol Chem
(2008,
283,
35258-35264)
copyright 2008.
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