spacer
spacer

PDBsum entry 2ce9

Go to PDB code: 
protein ligands Protein-protein interface(s) links
Transcription regulation PDB id
2ce9
Jmol PyMol
Contents
Protein chains
337 a.a. *
Ligands
MET-TRP-ARG-PRO-
TRP
×2
Waters ×861
* Residue conservation analysis
PDB id:
2ce9
Name: Transcription regulation
Title: A wrpw peptide bound to the groucho-tle wd40 domain.
Structure: Transducin-like enhancer protein 1. Chain: a, b, c, d. Fragment: partial sp and whole wd40 domains, residues 443-7 synonym: esg1, e(sp1) homolog. Engineered: yes. Wrpw peptide. Chain: x, y
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Synthetic: yes. Organism_taxid: 9606
Biol. unit: Trimer (from PDB file)
Resolution:
2.12Å     R-factor:   0.181     R-free:   0.244
Authors: L.M.Pickles,S.M.Roe,L.H.Pearl
Key ref:
B.H.Jennings et al. (2006). Molecular recognition of transcriptional repressor motifs by the WD domain of the Groucho/TLE corepressor. Mol Cell, 22, 645-655. PubMed id: 16762837 DOI: 10.1016/j.molcel.2006.04.024
Date:
03-Feb-06     Release date:   14-Jun-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q04724  (TLE1_HUMAN) -  Transducin-like enhancer protein 1
Seq:
Struc:
 
Seq:
Struc:
770 a.a.
337 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 7 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     nucleus   1 term 
  Biological process     regulation of transcription, DNA-dependent   1 term 

 

 
DOI no: 10.1016/j.molcel.2006.04.024 Mol Cell 22:645-655 (2006)
PubMed id: 16762837  
 
 
Molecular recognition of transcriptional repressor motifs by the WD domain of the Groucho/TLE corepressor.
B.H.Jennings, L.M.Pickles, S.M.Wainwright, S.M.Roe, L.H.Pearl, D.Ish-Horowicz.
 
  ABSTRACT  
 
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.
 
  Selected figure(s)  
 
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).
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.
 
  The above figures are reprinted by permission from Cell Press: Mol Cell (2006, 22, 645-655) copyright 2006.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21459326 C.J.Villanueva, H.Waki, C.Godio, R.Nielsen, W.L.Chou, L.Vargas, K.Wroblewski, C.Schmedt, L.C.Chao, R.Boyadjian, S.Mandrup, A.Hevener, E.Saez, and P.Tontonoz (2011).
TLE3 is a dual-function transcriptional coregulator of adipogenesis.
  Cell Metab, 13, 413-427.  
21468892 C.Xu, and J.Min (2011).
Structure and function of WD40 domain proteins.
  Protein Cell, 2, 202-214.
PDB codes: 3e0c 3fm0 3i2n 3ow8
20451393 C.U.Stirnimann, E.Petsalaki, R.B.Russell, and C.W.Müller (2010).
WD40 proteins propel cellular networks.
  Trends Biochem Sci, 35, 565-574.  
19374764 A.J.Robertson, C.Larroux, B.M.Degnan, and J.A.Coffman (2009).
The evolution of Runx genes II. The C-terminal Groucho recruitment motif is present in both eumetazoans and homoscleromorphs but absent in a haplosclerid demosponge.
  BMC Res Notes, 2, 59.  
19609323 A.W.Oliver, S.Swift, C.J.Lord, A.Ashworth, and L.H.Pearl (2009).
Structural basis for recruitment of BRCA2 by PALB2.
  EMBO Rep, 10, 990-996.
PDB codes: 2w18 3eu7
  20975914 D.S.Dalafave (2009).
Prediction of functional engrailed homology-1 protein motif from sequence.
  Bioinformation, 4, 229-232.  
19250647 I.Riz, H.J.Lee, K.K.Baxter, R.Behnam, T.S.Hawley, and R.G.Hawley (2009).
Transcriptional activation by TLX1/HOX11 involves Gro/TLE corepressors.
  Biochem Biophys Res Commun, 380, 361-365.  
19330799 J.A.Coffman (2009).
Is Runx a linchpin for developmental signaling in metazoans?
  J Cell Biochem, 107, 194-202.  
19460168 L.Arce, K.T.Pate, and M.L.Waterman (2009).
Groucho binds two conserved regions of LEF-1 for HDAC-dependent repression.
  BMC Cancer, 9, 159.  
19956621 M.Buscarlet, R.Hermann, R.Lo, Y.Tang, K.Joachim, and S.Stifani (2009).
Cofactor-activated phosphorylation is required for inhibition of cortical neuron differentiation by Groucho/TLE1.
  PLoS One, 4, e8107.  
19805071 S.Payankaulam, and D.N.Arnosti (2009).
Groucho corepressor functions as a cofactor for the Knirps short-range transcriptional repressor.
  Proc Natl Acad Sci U S A, 106, 17314-17319.  
18254933 B.H.Jennings, and D.Ish-Horowicz (2008).
The Groucho/TLE/Grg family of transcriptional co-repressors.
  Genome Biol, 9, 205.  
18034187 B.H.Jennings, S.M.Wainwright, and D.Ish-Horowicz (2008).
Differential in vivo requirements for oligomerization during Groucho-mediated repression.
  EMBO Rep, 9, 76-83.  
18721877 E.Cinnamon, and Z.Paroush (2008).
Context-dependent regulation of Groucho/TLE-mediated repression.
  Curr Opin Genet Dev, 18, 435-440.  
18773886 H.Lu, E.Kozhina, S.Mahadevaraju, D.Yang, F.W.Avila, and J.W.Erickson (2008).
Maternal Groucho and bHLH repressors amplify the dose-sensitive X chromosome signal in Drosophila sex determination.
  Dev Biol, 323, 248-260.  
19036929 J.Mieszczanek, M.de la Roche, and M.Bienz (2008).
A role of Pygopus as an anti-repressor in facilitating Wnt-dependent transcription.
  Proc Natl Acad Sci U S A, 105, 19324-19329.  
18945670 L.Shi, S.Ko, S.Kim, I.Echchgadda, T.S.Oh, C.S.Song, and B.Chatterjee (2008).
Loss of Androgen Receptor in Aging and Oxidative Stress through Myb Protooncoprotein-regulated Reciprocal Chromatin Dynamics of p53 and Poly(ADP-ribose) Polymerase PARP-1.
  J Biol Chem, 283, 36474-36485.  
18611861 M.Buscarlet, A.Perin, A.Laing, J.M.Brickman, and S.Stifani (2008).
Inhibition of Cortical Neuron Differentiation by Groucho/TLE1 Requires Interaction with WRPW, but Not Eh1, Repressor Peptides.
  J Biol Chem, 283, 24881-24888.  
18297730 N.Y.Martynova, F.M.Eroshkin, L.V.Ermolina, G.V.Ermakova, A.L.Korotaeva, K.M.Smurova, F.K.Gyoeva, and A.G.Zaraisky (2008).
The LIM-domain protein Zyxin binds the homeodomain factor Xanf1/Hesx1 and modulates its activity in the anterior neural plate of Xenopus laevis embryo.
  Dev Dyn, 237, 736-749.  
18551179 P.C.Chen, M.Kuraguchi, J.Velasquez, Y.Wang, K.Yang, R.Edwards, D.Gillen, W.Edelmann, R.Kucherlapati, and S.M.Lipkin (2008).
Novel roles for MLH3 deficiency and TLE6-like amplification in DNA mismatch repair-deficient gastrointestinal tumorigenesis and progression.
  PLoS Genet, 4, e1000092.  
18626661 X.Hu, H.Zhou, F.Hu, J.Xu, Y.Zhao, and X.Yu (2008).
Recognition and characterization of TGF-beta receptor interacting protein 1 (TRIP-1) containing WD40 repeats from Clonorchis sinensis by bioinformatics, cloning, and expression in Escherichia coli.
  Parasitol Res, 103, 1151-1158.  
18031354 A.C.Nagel, I.Wech, D.Schwinkendorf, and A.Preiss (2007).
Involvement of co-repressors Groucho and CtBP in the regulation of single-minded in Drosophila.
  Hereditas, 144, 195-205.  
17586813 A.Fischer, and M.Gessler (2007).
Delta-Notch--and then? Protein interactions and proposed modes of repression by Hes and Hey bHLH factors.
  Nucleic Acids Res, 35, 4583-4596.  
17898168 A.Orian, J.J.Delrow, A.E.Rosales Nieves, M.Abed, D.Metzger, Z.Paroush, R.N.Eisenman, and S.M.Parkhurst (2007).
A Myc-Groucho complex integrates EGF and Notch signaling to regulate neural development.
  Proc Natl Acad Sci U S A, 104, 15771-15776.  
18056429 E.Peden, E.Kimberly, K.Gengyo-Ando, S.Mitani, and D.Xue (2007).
Control of sex-specific apoptosis in C. elegans by the BarH homeodomain protein CEH-30 and the transcriptional repressor UNC-37/Groucho.
  Genes Dev, 21, 3195-3207.  
17643306 M.Buscarlet, and S.Stifani (2007).
The 'Marx' of Groucho on development and disease.
  Trends Cell Biol, 17, 353-361.  
17803917 M.Ptashne (2007).
Repressors.
  Curr Biol, 17, R740-R741.  
17138566 S.Yaklichkin, A.B.Steiner, Q.Lu, and D.S.Kessler (2007).
FoxD3 and Grg4 physically interact to repress transcription and induce mesoderm in Xenopus.
  J Biol Chem, 282, 2548-2557.  
17598915 S.Yaklichkin, A.Vekker, S.Stayrook, M.Lewis, and D.S.Kessler (2007).
Prevalence of the EH1 Groucho interaction motif in the metazoan Fox family of transcriptional regulators.
  BMC Genomics, 8, 201.  
17060451 T.Heimbucher, C.Murko, B.Bajoghli, N.Aghaallaei, A.Huber, R.Stebegg, D.Eberhard, M.Fink, A.Simeone, and T.Czerny (2007).
Gbx2 and Otx2 interact with the WD40 domain of Groucho/Tle corepressors.
  Mol Cell Biol, 27, 340-351.  
17964267 T.Sekiya, and K.S.Zaret (2007).
Repression by Groucho/TLE/Grg proteins: genomic site recruitment generates compacted chromatin in vitro and impairs activator binding in vivo.
  Mol Cell, 28, 291-303.  
17937919 Z.Han, X.Xing, M.Hu, Y.Zhang, P.Liu, and J.Chai (2007).
Structural basis of EZH2 recognition by EED.
  Structure, 15, 1306-1315.
PDB code: 2qxv
17041588 L.A.Higa, M.Wu, T.Ye, R.Kobayashi, H.Sun, and H.Zhang (2006).
CUL4-DDB1 ubiquitin ligase interacts with multiple WD40-repeat proteins and regulates histone methylation.
  Nat Cell Biol, 8, 1277-1283.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.

 

spacer

spacer