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PDBsum entry 2vpd
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protein metals Protein-protein interface(s) links
Gene regulation PDB id
2vpd

 

 

 

 

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Contents
Protein chains
59 a.a. *
34 a.a. *
66 a.a. *
35 a.a. *
Metals
_ZN ×4
Waters ×17
* Residue conservation analysis
PDB id:
2vpd
Name: Gene regulation
Title: Decoding of methylated histone h3 tail by the pygo-bcl9 wnt signaling complex
Structure: Pygopus homolog 1. Chain: a, c. Fragment: phd domain, residues 333-398. Synonym: hpygo1. Engineered: yes. B-cell cll/lymphoma 9 protein. Chain: b, d. Fragment: hd1 domain, residues 174-205. Synonym: bcl9, b-cell lymphoma 9 protein, protein legless homolog.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 511693. Expression_system_variant: codonplus(de3)-ril.
Resolution:
2.77Å     R-factor:   0.235     R-free:   0.267
Authors: M.Fiedler,M.J.Sanchez-Barrena,M.Nekrasov,J.Mieszczanek,V.Rybin, J.Muller,P.Evans,M.Bienz
Key ref:
M.Fiedler et al. (2008). Decoding of methylated histone H3 tail by the Pygo-BCL9 Wnt signaling complex. Mol Cell, 30, 507-518. PubMed id: 18498752 DOI: 10.1016/j.molcel.2008.03.011
Date:
27-Feb-08     Release date:   17-Jun-08    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q9Y3Y4  (PYGO1_HUMAN) -  Pygopus homolog 1 from Homo sapiens
Seq:
Struc: 		419 a.a.
59 a.a.
Protein chain
Pfam   ArchSchema ?
O00512  (BCL9_HUMAN) -  B-cell CLL/lymphoma 9 protein from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		1426 a.a.
34 a.a.*
Protein chain
Pfam   ArchSchema ?
Q9Y3Y4  (PYGO1_HUMAN) -  Pygopus homolog 1 from Homo sapiens
Seq:
Struc: 		419 a.a.
66 a.a.*
Protein chain
Pfam   ArchSchema ?
O00512  (BCL9_HUMAN) -  B-cell CLL/lymphoma 9 protein from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		1426 a.a.
35 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 6 residue positions (black crosses)

 

 
DOI no: 10.1016/j.molcel.2008.03.011 Mol Cell 30:507-518 (2008)
PubMed id: 18498752  
 
 
Decoding of methylated histone H3 tail by the Pygo-BCL9 Wnt signaling complex.
M.Fiedler, M.J.Sánchez-Barrena, M.Nekrasov, J.Mieszczanek, V.Rybin, J.Müller, P.Evans, M.Bienz.
 
  ABSTRACT  
 
Pygo and BCL9/Legless transduce the Wnt signal by promoting the transcriptional activity of beta-catenin/Armadillo in normal and malignant cells. We show that human and Drosophila Pygo PHD fingers associate with their cognate HD1 domains from BCL9/Legless to bind specifically to the histone H3 tail methylated at lysine 4 (H3K4me). The crystal structures of ternary complexes between PHD, HD1, and two different H3K4me peptides reveal a unique mode of histone tail recognition: efficient histone binding requires HD1 association, and the PHD-HD1 complex binds preferentially to H3K4me2 while displaying insensitivity to methylation of H3R2. Therefore, this is a prime example of histone tail binding by a PHD finger (of Pygo) being modulated by a cofactor (BCL9/Legless). Rescue experiments in Drosophila indicate that Wnt signaling outputs depend on histone decoding. The specificity of this process provided by the Pygo-BCL9/Legless complex suggests that this complex facilitates an early step in the transition from gene silence to Wnt-induced transcription.
 
  Selected figure(s)  
 
Figure 4.
Structures of the Ternary Complex, and H3K4me-Binding Cavities (A) Molecular surface representation of hPHD-HD1 binding to H3K4me2 (in yellow cylinder style), with W366 and other critical residues labeled. (B and C) Cylinder representations of (B) semiaromatic K4me2 cavity and (C) A1 cavity, with critical H bonds indicated as dotted lines and hydrophobic contacts as double brackets. (D) Molecular surface representation of PHD, revealing solvent exposure of R2 (regardless of its methylation status). H3K4me, yellow; PHD cavity residues, green. Note that Tern2 has essentially the same structure as Tern1 (shown here; see text). (E) Binding constants of various hPHD point mutants for H3K4me3 15-mer (K[d] values in [mu]M; see also Figure 3 Figure 3-). Mol Cell. 2008 May 23; 30(4-2): 507–518. doi: 10.1016/j.molcel.2008.03.011. Copyright [copyright] 2008 ELL & Excerpta Medica
Figure 5.
Buttressing of the PHD A1 Cavity by HD1 (A) Molecular surface representation of PHD (green) with electrostatic potential, facing A1 cavity (left, yellow) and HD1 (right, orange). (B) Buttressing of A1 cavity of PHD (molecular surface representation with electrostatic potential) by HD1 (ribbon representation). D352 lip residue of the K4me2 cavity and E360 residue critical for A1 anchoring are indicated. Mol Cell. 2008 May 23; 30(4-2): 507–518. doi: 10.1016/j.molcel.2008.03.011. Copyright [copyright] 2008 ELL & Excerpta Medica
 
  The above figures are reprinted from an Open Access publication published by Cell Press: Mol Cell (2008, 30, 507-518) copyright 2008.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21338586 J.Yu, D.Qi, M.Xing, R.Li, K.Jiang, Y.Peng, and D.Cui (2011).
MK-801 induces schizophrenic behaviors through downregulating Wnt signaling pathways in male mice.
  Brain Res, 1385, 281-292.  
21059680 P.Slama, and D.Geman (2011).
Identification of family-determining residues in PHD fingers.
  Nucleic Acids Res, 39, 1666-1679.  
20564229 B.Gu, K.Watanabe, and X.Dai (2010).
Epithelial stem cells: an epigenetic and Wnt-centric perspective.
  J Cell Biochem, 110, 1279-1287.  
20439429 H.Song, S.Goetze, J.Bischof, C.Spichiger-Haeusermann, M.Kuster, E.Brunner, and K.Basler (2010).
Coop functions as a corepressor of Pangolin and antagonizes Wingless signaling.
  Genes Dev, 24, 881-886.  
20923397 K.L.Yap, and M.M.Zhou (2010).
Keeping it in the family: diverse histone recognition by conserved structural folds.
  Crit Rev Biochem Mol Biol, 45, 488-505.  
  20473358 L.B.Bennett, K.H.Taylor, G.L.Arthur, F.B.Rahmatpanah, S.I.Hooshmand, and C.W.Caldwell (2010).
Epigenetic regulation of WNT signaling in chronic lymphocytic leukemia.
  Epigenomics, 2, 53-70.  
20574448 P.Chi, C.D.Allis, and G.G.Wang (2010).
Covalent histone modifications--miswritten, misinterpreted and mis-erased in human cancers.
  Nat Rev Cancer, 10, 457-469.  
20837152 P.Wend, J.D.Holland, U.Ziebold, and W.Birchmeier (2010).
Wnt signaling in stem and cancer stem cells.
  Semin Cell Dev Biol, 21, 855-863.  
20213668 R.J.Falconer, A.Penkova, I.Jelesarov, and B.M.Collins (2010).
Survey of the year 2008: applications of isothermal titration calorimetry.
  J Mol Recognit, 23, 395-413.  
20637214 T.C.Miller, T.J.Rutherford, C.M.Johnson, M.Fiedler, and M.Bienz (2010).
Allosteric remodelling of the histone H3 binding pocket in the Pygo2 PHD finger triggered by its binding to the B9L/BCL9 co-factor.
  J Mol Biol, 401, 969-984.
PDB code: 2xb1
19487454 B.Gu, P.Sun, Y.Yuan, R.C.Moraes, A.Li, A.Teng, A.Agrawal, C.Rhéaume, V.Bilanchone, J.M.Veltmaat, K.Takemaru, S.Millar, E.Y.Lee, M.T.Lewis, B.Li, and X.Dai (2009).
Pygo2 expands mammary progenitor cells by facilitating histone H3 K4 methylation.
  J Cell Biol, 185, 811-826.  
19619488 B.T.MacDonald, K.Tamai, and X.He (2009).
Wnt/beta-catenin signaling: components, mechanisms, and diseases.
  Dev Cell, 17, 9.  
19624289 C.A.Musselman, R.E.Mansfield, A.L.Garske, F.Davrazou, A.H.Kwan, S.S.Oliver, H.O'Leary, J.M.Denu, J.P.Mackay, and T.G.Kutateladze (2009).
Binding of the CHD4 PHD2 finger to histone H3 is modulated by covalent modifications.
  Biochem J, 423, 179-187.  
20048137 C.A.Musselman, and T.G.Kutateladze (2009).
PHD fingers: epigenetic effectors and potential drug targets.
  Mol Interv, 9, 314-323.  
19305417 C.Mosimann, G.Hausmann, and K.Basler (2009).
Beta-catenin hits chromatin: regulation of Wnt target gene activation.
  Nat Rev Mol Cell Biol, 10, 276-286.  
19293276 F.Chignola, M.Gaetani, A.Rebane, T.Org, L.Mollica, C.Zucchelli, A.Spitaleri, V.Mannella, P.Peterson, and G.Musco (2009).
The solution structure of the first PHD finger of autoimmune regulator in complex with non-modified histone H3 tail reveals the antagonistic role of H3R2 methylation.
  Nucleic Acids Res, 37, 2951-2961.
PDB code: 2ke1
19046988 H.O.Kalkman (2009).
Altered growth factor signaling pathways as the basis of aberrant stem cell maturation in schizophrenia.
  Pharmacol Ther, 121, 115-122.  
  20066091 K.M.Cadigan, and M.Peifer (2009).
Wnt signaling from development to disease: insights from model systems.
  Cold Spring Harbor Perspect Biol, 1, a002881.  
19442115 K.S.Champagne, and T.G.Kutateladze (2009).
Structural insight into histone recognition by the ING PHD fingers.
  Curr Drug Targets, 10, 432-441.  
19234526 M.A.Adams-Cioaba, and J.Min (2009).
Structure and function of histone methylation binding proteins.
  Biochem Cell Biol, 87, 93.  
19555349 P.G.Andrews, Z.He, C.Popadiuk, and K.R.Kao (2009).
The transcriptional activity of Pygopus is enhanced by its interaction with cAMP-response-element-binding protein (CREB)-binding protein.
  Biochem J, 422, 493-501.  
19446523 S.Chakravarty, L.Zeng, and M.M.Zhou (2009).
Structure and site-specific recognition of histone H3 by the PHD finger of human autoimmune regulator.
  Structure, 17, 670-679.
PDB code: 2kft
19744855 T.J.Gibson (2009).
Cell regulation: determined to signal discrete cooperation.
  Trends Biochem Sci, 34, 471-482.  
19487452 V.Horsley (2009).
Epigenetics, Wnt signaling, and stem cells: the Pygo2 connection.
  J Cell Biol, 185, 761-763.  
  19011376 G.Musco, and P.Peterson (2008).
PHD finger of autoimmune regulator: An epigenetic link between the histone modifications and tissue-specific antigen expression in thymus.
  Epigenetics, 3, 310-314.  
19056888 K.A.Jones, and C.R.Kemp (2008).
Wnt-induced proteolytic targeting.
  Genes Dev, 22, 3077-3081.  
18627596 M.de la Roche, J.Worm, and M.Bienz (2008).
The function of BCL9 in Wnt/beta-catenin signaling and colorectal cancer cells.
  BMC Cancer, 8, 199.  
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 code is shown on the right.

 

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