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5fht

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Revision as of 07:20, 6 May 2020

HtrA2 protease mutant V226K

Structural highlights

5fht is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
Gene:	HTRA2, OMI, PRSS25 (HUMAN)
Activity:	HtrA2 peptidase, with EC number 3.4.21.108
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

Publication Abstract from PubMed

HtrA2(Omi) protease controls protein quality in mitochondria and plays a major role in apoptosis. Its HtrA2S306A mutant (with the catalytic serine routinely disabled for an X-ray study to avoid self-degradation) is a homotrimer whose subunits contain the serine protease domain (PD) and the regulatory PDZ domain. In the inactive state, a tight interdomain interface limits penetration of both PDZ-activating ligands and PD substrates into their respective target sites. We successfully crystalized HtrA2V226K/S306A, whose active counterpart HtrA2V226K has had higher proteolytic activity, suggesting higher propensity to opening the PD-PDZ interface than that of the wild type HtrA2. Yet, the crystal structure revealed the HtrA2V226K/S306A architecture typical of the inactive protein. To get a consistent interpretation of crystallographic data in the light of kinetic results, we employed molecular dynamics (MD). V325D inactivating mutant was used as a reference. Our simulations demonstrated that upon binding of a specific peptide ligand NH2-GWTMFWV-COOH, the PDZ domains open more dynamically in the wild type protease compared to the V226K mutant, whereas the movement is not observed in the V325D mutant. The movement relies on a PDZ vs. PD rotation which opens the PD-PDZ interface in a lid-like (budding flower-like in trimer) fashion. The noncovalent hinges A and B are provided by two clusters of interfacing residues, harboring V325D and V226K in the C- and N-terminal PD barrels, respectively. The opening of the subunit interfaces progresses in a sequential manner during the 50 ns MD simulation. In the systems without the ligand only minor PDZ shifts relative to PD are observed, but the interface does not open. Further activation-associated events, e.g. PDZ-L3 positional swap seen in any active HtrA protein (vs. HtrA2), were not observed. In summary, this study provides hints on the mechanism of activation of wtHtrA2, the dynamics of the inactive HtrA2V325D, but does not allow to explain an increased activity of HtrA2V226K.

Distinct 3D Architecture and Dynamics of the Human HtrA2(Omi) Protease and Its Mutated Variants.,Gieldon A, Zurawa-Janicka D, Jarzab M, Wenta T, Golik P, Dubin G, Lipinska B, Ciarkowski J PLoS One. 2016 Aug 29;11(8):e0161526. doi: 10.1371/journal.pone.0161526., eCollection 2016. PMID:27571206^[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
↑ Gieldon A, Zurawa-Janicka D, Jarzab M, Wenta T, Golik P, Dubin G, Lipinska B, Ciarkowski J. Distinct 3D Architecture and Dynamics of the Human HtrA2(Omi) Protease and Its Mutated Variants. PLoS One. 2016 Aug 29;11(8):e0161526. doi: 10.1371/journal.pone.0161526., eCollection 2016. PMID:27571206 doi:http://dx.doi.org/10.1371/journal.pone.0161526

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5fht"

@@ Line 1: / Line 1: @@
 ==HtrA2 protease mutant V226K==
-<StructureSection load='5fht' size='340' side='right' caption='[[5fht]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
+<StructureSection load='5fht' size='340' side='right'caption='[[5fht]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5fht]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5FHT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5FHT FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5fht]] is a 1 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=5FHT OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5FHT FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HTRA2, OMI, PRSS25 ([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=5fht FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fht OCA], [http://pdbe.org/5fht PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5fht RCSB], [http://www.ebi.ac.uk/pdbsum/5fht PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5fht ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5fht FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fht OCA], [http://pdbe.org/5fht PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5fht RCSB], [http://www.ebi.ac.uk/pdbsum/5fht PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5fht ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 21: / Line 22: @@
 </div>
 <div class="pdbe-citations 5fht" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Proteinase|Proteinase]]
+*[[Proteinase 3D structures|Proteinase 3D structures]]
 == References ==
 <references/>
@@ Line 26: / Line 31: @@
 </StructureSection>
 [[Category: HtrA2 peptidase]]
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Ciarkowski, A]]
 [[Category: Dubin, G]]

5fht

From Proteopedia

Revision as of 07:20, 6 May 2020

HtrA2 protease mutant V226K

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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