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PDBsum entry 6vee
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Peptide binding protein
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PDB id
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6vee
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References listed in PDB file
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Key reference
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Title
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Alternative splicing and allosteric regulation modulate the chromatin binding of uhrf1.
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Authors
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M.Tauber,
S.Kreuz,
A.Lemak,
P.Mandal,
Z.Yerkesh,
A.Veluchamy,
B.Al-Gashgari,
A.Aljahani,
L.V.Cortés-Medina,
D.Azhibek,
L.Fan,
M.S.Ong,
S.Duan,
S.Houliston,
C.H.Arrowsmith,
W.Fischle.
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Ref.
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Nucleic Acids Res, 2020,
48,
7728-7747.
[DOI no: ]
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PubMed id
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Abstract
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UHRF1 is an important epigenetic regulator associated with apoptosis and tumour
development. It is a multidomain protein that integrates readout of different
histone modification states and DNA methylation with enzymatic histone
ubiquitylation activity. Emerging evidence indicates that the chromatin-binding
and enzymatic modules of UHRF1 do not act in isolation but interplay in a
coordinated and regulated manner. Here, we compared two splicing variants (V1,
V2) of murine UHRF1 (mUHRF1) with human UHRF1 (hUHRF1). We show that insertion
of nine amino acids in a linker region connecting the different TTD and PHD
histone modification-binding domains causes distinct H3K9me3-binding behaviour
of mUHRF1 V1. Structural analysis suggests that in mUHRF1 V1, in contrast to V2
and hUHRF1, the linker is anchored in a surface groove of the TTD domain,
resulting in creation of a coupled TTD-PHD module. This establishes multivalent,
synergistic H3-tail binding causing distinct cellular localization and enhanced
H3K9me3-nucleosome ubiquitylation activity. In contrast to hUHRF1,
H3K9me3-binding of the murine proteins is not allosterically regulated by
phosphatidylinositol 5-phosphate that interacts with a separate less-conserved
polybasic linker region of the protein. Our results highlight the importance of
flexible linkers in regulating multidomain chromatin binding proteins and point
to divergent evolution of their regulation.
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