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PDBsum entry 2ce8
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Transcription regulation
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PDB id
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2ce8
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References listed in PDB file
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Key reference
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Title
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Molecular recognition of transcriptional repressor motifs by the wd domain of the groucho/tle corepressor.
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Authors
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B.H.Jennings,
L.M.Pickles,
S.M.Wainwright,
S.M.Roe,
L.H.Pearl,
D.Ish-Horowicz.
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Ref.
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Mol Cell, 2006,
22,
645-655.
[DOI no: ]
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PubMed id
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Abstract
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The Groucho (Gro)/TLE/Grg family of corepressors operates in many signaling
pathways (including Notch and Wnt). Gro/TLE proteins recognize a wide range of
transcriptional repressors by binding to divergent short peptide sequences,
including a C-terminal WRPW/Y motif (Hairy/Hes/Runx) and internal eh1 motifs
(FxIxxIL; Engrailed/Goosecoid/Pax/Nkx). Here, we identify several missense
mutations in Drosophila Gro, which demonstrate peptide binding to the central
pore of the WD (WD40) beta propeller domain in vitro and in vivo. We define
these interactions at the molecular level with crystal structures of the WD
domain of human TLE1 bound to either WRPW or eh1 peptides. The two distinct
peptide motifs adopt markedly different bound conformations but occupy
overlapping sites across the central pore of the beta propeller. Our structural
and functional analysis explains the rigid conservation of the WRPW motif, the
sequence flexibility of eh1 motifs, and other aspects of repressor recognition
by Gro in vivo.
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Figure 4.
Figure 4. Binding of the WRPW and eh1 Peptide Motifs to the
TLE-WD Domain
(A) Backbone of the SMWRPW peptide (purple)
from human Hes1 on TLE-WD (ribbons) showing that binding occurs
across the pore.
(B) Close-up view of the WPRW core
revealing its compact orientation.
(C) Detailed
intermolecular interactions between the WRPW core and adjacent
amino acids in the WD domain. L743, corresponding to the
aminoacid mutated in MB31, is underlined.
(D) The eh1
peptide backbone (purple) from human Gsc on TLE-WD (ribbons)
indicating the site of peptide binding and its α-helical
structure.
(E) Close-up view of the eh1 core heptapeptide
showing its elongated structure.
(F) Detailed
intermolecular interactions between the core peptide and
adjacent aminoacids in the WD domain showing that contacts are
made to the similar amino acids as for WRPW (C).
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Figure 5.
Figure 5. Common Conformational Features of Bound WRPW and
eh1 Motifs
Superposition of the WRPW and eh1 peptides in
their bound conformations, showing the analogous positions
adopted by the Trp-1 and Phe-2, respectively. Trp-4 from WRPW
overlies the side chains of Ile-3 and Leu-7 from eh1.
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The above figures are
reprinted
by permission from Cell Press:
Mol Cell
(2006,
22,
645-655)
copyright 2006.
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Secondary reference #1
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Title
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Crystal structure of the c-Terminal wd40 repeat domain of the human groucho/tle1 transcriptional corepressor.
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Authors
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L.M.Pickles,
S.M.Roe,
E.J.Hemingway,
S.Stifani,
L.H.Pearl.
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Ref.
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Structure, 2002,
10,
751-761.
[DOI no: ]
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PubMed id
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Figure 1.
Figure 1. Domain Structure of Groucho/TLE ProteinsSchematic
diagram of the defined domains in Gro/TLE corepressors.
Glutamine-rich Q domain; glycine/proline-rich GP domain; CcN
domain containing nuclear localization and phosphorylation
sites; serine/threonine-proline-rich SP domain; and WD40 repeat
domain. Residue numbers defining domain boundaries are for human
TLE1. Regions of Groucho/TLE proteins implicated in interaction
with transcription factors are indicated below (horizontal
lines), while those implicated in interactions with repression
effectors are indicated above. In many cases, involvement of a
particular region of Gro/TLE has only been defined by loss of
function on deletion of that region, and not by positive
demonstration of interaction.
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The above figure is
reproduced from the cited reference
with permission from Cell Press
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