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PDBsum entry 6bw3
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Gene regulation
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PDB id
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6bw3
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References listed in PDB file
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Key reference
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Title
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Direct interaction between the prdm3 and prdm16 tumor suppressors and the nurd chromatin remodeling complex.
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Authors
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D.Ivanochko,
L.Halabelian,
E.Henderson,
P.Savitsky,
H.Jain,
E.Marcon,
S.Duan,
A.Hutchinson,
A.Seitova,
D.Barsyte-Lovejoy,
P.Filippakopoulos,
J.Greenblatt,
E.Lima-Fernandes,
C.H.Arrowsmith.
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Ref.
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Nucleic Acids Res, 2019,
47,
1225-1238.
[DOI no: ]
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PubMed id
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Abstract
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Aberrant isoform expression of chromatin-associated proteins can induce
epigenetic programs related to disease. The MDS1 and EVI1 complex locus (MECOM)
encodes PRDM3, a protein with an N-terminal PR-SET domain, as well as a shorter
isoform, EVI1, lacking the N-terminus containing the PR-SET domain (ΔPR).
Imbalanced expression of MECOM isoforms is observed in multiple malignancies,
implicating EVI1 as an oncogene, while PRDM3 has been suggested to function as a
tumor suppressor through an unknown mechanism. To elucidate functional
characteristics of these N-terminal residues, we compared the protein
interactomes of the full-length and ΔPR isoforms of PRDM3 and its closely
related paralog, PRDM16. Unlike the ΔPR isoforms, both full-length isoforms
exhibited a significantly enriched association with components of the NuRD
chromatin remodeling complex, especially RBBP4. Typically, RBBP4 facilitates
chromatin association of the NuRD complex by binding to histone H3 tails. We
show that RBBP4 binds to the N-terminal amino acid residues of PRDM3 and PRDM16,
with a dissociation constant of 3.0 μM, as measured by isothermal titration
calorimetry. Furthermore, high-resolution X-ray crystal structures of PRDM3 and
PRDM16 N-terminal peptides in complex with RBBP4 revealed binding to RBBP4
within the conserved histone H3-binding groove. These data support a mechanism
of isoform-specific interaction of PRDM3 and PRDM16 with the NuRD chromatin
remodeling complex.
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