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PDBsum entry 2pzd

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protein ligands Protein-protein interface(s) links
Hydrolase PDB id
2pzd
Jmol
Contents
Protein chain
106 a.a. *
Ligands
EDO ×2
Waters ×9
* Residue conservation analysis
PDB id:
2pzd
Name: Hydrolase
Title: Crystal structure of the htra2/omi pdz domain bound to a pha ligand (wtmfwv)
Structure: Serine protease htra2. Chain: a, b. Synonym: high temperature requirement protein a2, htra2, om regulated endoprotease, serine proteinase omi, serine prote engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: htra2. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
2.75Å     R-factor:   0.210     R-free:   0.254
Authors: B.A.Appleton,C.Wiesmann
Key ref:
Y.Zhang et al. (2007). Structural and functional analysis of the ligand specificity of the HtrA2/Omi PDZ domain. Protein Sci, 16, 1738-1750. PubMed id: 17656586 DOI: 10.1110/ps.072833207
Date:
17-May-07     Release date:   07-Aug-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
O43464  (HTRA2_HUMAN) -  Serine protease HTRA2, mitochondrial
Seq:
Struc:
458 a.a.
106 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.3.4.21.108  - HtrA2 peptidase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

 

 
DOI no: 10.1110/ps.072833207 Protein Sci 16:1738-1750 (2007)
PubMed id: 17656586  
 
 
Structural and functional analysis of the ligand specificity of the HtrA2/Omi PDZ domain.
Y.Zhang, B.A.Appleton, P.Wu, C.Wiesmann, S.S.Sidhu.
 
  ABSTRACT  
 
The mitochondrial serine protease HtrA2/Omi helps to maintain mitochondrial function by handling misfolded proteins in the intermembrane space. In addition, HtrA2/Omi has been implicated as a proapoptotic factor upon release into the cytoplasm during the cell death cascade. The protein contains a C-terminal PDZ domain that packs against the protease active site and inhibits proteolytic activity. Engagement of the PDZ domain by peptide ligands has been shown to activate the protease and also has been proposed to mediate substrate recognition. We report a detailed structural and functional analysis of the human HtrA2/Omi PDZ domain using peptide libraries and affinity assays to define specificity, X-ray crystallography to view molecular details of PDZ-ligand interactions, and alanine-scanning mutagenesis to probe the peptide-binding groove. We show that the HtrA2/Omi PDZ domain recognizes both C-terminal and internal stretches of extended, hydrophobic polypeptides. High-affinity ligand recognition requires contacts with up to five hydrophobic side chains by distinct sites on the PDZ domain. However, no particular residue type is absolutely required at any position, and thus, the HtrA2/Omi PDZ domain appears to be a promiscuous module adapted to recognize unstructured, hydrophobic polypeptides. This type of specificity is consistent with the biological role of HtrA2/Omi in mitochondria, which requires the recognition of diverse, exposed stretches of hydrophobic sequences in misfolded proteins. The findings are less consistent with, but do not exclude, a role for the PDZ domain in targeting the protease to specific substrates during apoptosis.
 
  Selected figure(s)  
 
Figure 2.
Figure 2. The HtrA2-PDZ crystal structure. (A) Dimer of HtrA2-PDZext;
Figure 4.
Figure 4. Results of shotgun alanine scanning mapped on the structure of
 
  The above figures are reprinted by permission from the Protein Society: Protein Sci (2007, 16, 1738-1750) copyright 2007.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21353780 B.M.Baker, and C.M.Haynes (2011).
Mitochondrial protein quality control during biogenesis and aging.
  Trends Biochem Sci, 36, 254-261.  
21247409 H.Schuhmann, U.Mogg, and I.Adamska (2011).
A new principle of oligomerization of plant DEG7 protease based on interactions of degenerated protease domains.
  Biochem J, 435, 167-174.  
20509869 H.J.Lee, and J.J.Zheng (2010).
PDZ domains and their binding partners: structure, specificity, and modification.
  Cell Commun Signal, 8, 8.  
  21072759 L.Cesaro, and M.Salvi (2010).
Mitochondrial tyrosine phosphoproteome: new insights from an up-to-date analysis.
  Biofactors, 36, 437-450.  
19763263 F.Johnson, and M.G.Kaplitt (2009).
Novel mitochondrial substrates of omi indicate a new regulatory role in neurodegenerative disorders.
  PLoS One, 4, e7100.  
19668863 P.Hauske, N.Mamant, S.Hasenbein, S.Nickel, C.Ottmann, T.Clausen, M.Ehrmann, and M.Kaiser (2009).
Peptidic small molecule activators of the stress sensor DegS.
  Mol Biosyst, 5, 980-985.  
19569188 T.Beuming, R.Farid, and W.Sherman (2009).
High-energy water sites determine peptide binding affinity and specificity of PDZ domains.
  Protein Sci, 18, 1609-1619.  
18239672 B.P.Eckelman, M.Drag, S.J.Snipas, and G.S.Salvesen (2008).
The mechanism of peptide-binding specificity of IAP BIR domains.
  Cell Death Differ, 15, 920-928.  
18174901 L.Vande Walle, M.Lamkanfi, and P.Vandenabeele (2008).
The mitochondrial serine protease HtrA2/Omi: an overview.
  Cell Death Differ, 15, 453-460.  
18828675 R.Tonikian, Y.Zhang, S.L.Sazinsky, B.Currell, J.H.Yeh, B.Reva, H.A.Held, B.A.Appleton, M.Evangelista, Y.Wu, X.Xin, A.C.Chan, S.Seshagiri, L.A.Lasky, C.Sander, C.Boone, G.D.Bader, and S.S.Sidhu (2008).
A specificity map for the PDZ domain family.
  PLoS Biol, 6, e239.  
18505836 T.Krojer, K.Pangerl, J.Kurt, J.Sawa, C.Stingl, K.Mechtler, R.Huber, M.Ehrmann, and T.Clausen (2008).
Interplay of PDZ and protease domain of DegP ensures efficient elimination of misfolded proteins.
  Proc Natl Acad Sci U S A, 105, 7702-7707.  
17975547 E.S.Alnemri (2007).
HtrA2 and Parkinson's disease: think PINK?
  Nat Cell Biol, 9, 1227-1229.  
17962403 S.T.Runyon, Y.Zhang, B.A.Appleton, S.L.Sazinsky, P.Wu, B.Pan, C.Wiesmann, N.J.Skelton, and S.S.Sidhu (2007).
Structural and functional analysis of the PDZ domains of human HtrA1 and HtrA3.
  Protein Sci, 16, 2454-2471.
PDB codes: 2joa 2p3w
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.