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2pzd

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Revision as of 04:35, 10 September 2015

Crystal Structure of the HtrA2/Omi PDZ Domain Bound to a Phage-Derived Ligand (WTMFWV)

Structural highlights

2pzd is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	2joa, 2p3w
Gene:	HTRA2 (HUMAN)
Activity:	HtrA2 peptidase, with EC number 3.4.21.108
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum

Disease

[HTRA2_HUMAN] Defects in HTRA2 are the cause of Parkinson disease type 13 (PARK13) [MIM:610297]. A complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability, as well as by a clinically significant response to treatment with levodopa. The pathology involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain.^[1] ^[2]

Function

[HTRA2_HUMAN] Serine protease that shows proteolytic activity against a non-specific substrate beta-casein. Promotes or induces cell death either by direct binding to and inhibition of BIRC proteins (also called inhibitor of apoptosis proteins, IAPs), leading to an increase in caspase activity, or by a BIRC inhibition-independent, caspase-independent and serine protease activity-dependent mechanism. Cleaves THAP5 and promotes its degradation during apoptosis. Isoform 2 seems to be proteolytically inactive.^[3] ^[4]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

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.

Structural and functional analysis of the ligand specificity of the HtrA2/Omi PDZ domain.,Zhang Y, Appleton BA, Wu P, Wiesmann C, Sidhu SS Protein Sci. 2007 Aug;16(8):1738-50. PMID:17656586^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Strauss KM, Martins LM, Plun-Favreau H, Marx FP, Kautzmann S, Berg D, Gasser T, Wszolek Z, Muller T, Bornemann A, Wolburg H, Downward J, Riess O, Schulz JB, Kruger R. Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease. Hum Mol Genet. 2005 Aug 1;14(15):2099-111. Epub 2005 Jun 16. PMID:15961413 doi:10.1093/hmg/ddi215
↑ Bogaerts V, Nuytemans K, Reumers J, Pals P, Engelborghs S, Pickut B, Corsmit E, Peeters K, Schymkowitz J, De Deyn PP, Cras P, Rousseau F, Theuns J, Van Broeckhoven C. Genetic variability in the mitochondrial serine protease HTRA2 contributes to risk for Parkinson disease. Hum Mutat. 2008 Jun;29(6):832-40. PMID:18401856 doi:10.1002/humu.20713
↑ Bartke T, Pohl C, Pyrowolakis G, Jentsch S. Dual role of BRUCE as an antiapoptotic IAP and a chimeric E2/E3 ubiquitin ligase. Mol Cell. 2004 Jun 18;14(6):801-11. PMID:15200957 doi:10.1016/j.molcel.2004.05.018
↑ Balakrishnan MP, Cilenti L, Mashak Z, Popat P, Alnemri ES, Zervos AS. THAP5 is a human cardiac-specific inhibitor of cell cycle that is cleaved by the proapoptotic Omi/HtrA2 protease during cell death. Am J Physiol Heart Circ Physiol. 2009 Aug;297(2):H643-53. doi:, 10.1152/ajpheart.00234.2009. Epub 2009 Jun 5. PMID:19502560 doi:10.1152/ajpheart.00234.2009
↑ Zhang Y, Appleton BA, Wu P, Wiesmann C, Sidhu SS. Structural and functional analysis of the ligand specificity of the HtrA2/Omi PDZ domain. Protein Sci. 2007 Aug;16(8):1738-50. PMID:17656586 doi:http://dx.doi.org/16/8/1738

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2pzd"

@@ Line 2: / Line 2: @@
 <StructureSection load='2pzd' size='340' side='right' caption='[[2pzd]], [[Resolution|resolution]] 2.75&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2pzd]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2PZD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2PZD FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2pzd]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2PZD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2PZD FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2joa|2joa]], [[2p3w|2p3w]]</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HTRA2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HTRA2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/HtrA2_peptidase HtrA2 peptidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.108 3.4.21.108] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2pzd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2pzd OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2pzd RCSB], [http://www.ebi.ac.uk/pdbsum/2pzd PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2pzd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2pzd OCA], [http://pdbe.org/2pzd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2pzd RCSB], [http://www.ebi.ac.uk/pdbsum/2pzd PDBsum]</span></td></tr>
 </table>
 == Disease ==
@@ Line 31: / Line 31: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 2pzd" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
 [[Category: HtrA2 peptidase]]
+[[Category: Human]]
 [[Category: Appleton, B A]]
 [[Category: Wiesmann, C]]

2pzd

From Proteopedia

Revision as of 04:35, 10 September 2015

Crystal Structure of the HtrA2/Omi PDZ Domain Bound to a Phage-Derived Ligand (WTMFWV)

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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