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5to0

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Revision as of 12:14, 23 September 2020

HTRA2 S276C mutant

Structural highlights

5to0 is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	5m3n, 5m3o, 5tnz, 5tny, 5to1
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 (high-temperature requirement 2) is a human mitochondrial protease that has a role in apoptosis and Parkinson's disease. The structure of HtrA2 with an intact catalytic triad was determined, revealing a conformational change in the active site loops, involving mainly the regulatory LD loop, which resulted in burial of the catalytic serine relative to the previously reported structure of the proteolytically inactive mutant. Mutations in the loops surrounding the active site that significantly restricted their mobility, reduced proteolytic activity both in vitro and in cells, suggesting that regulation of HtrA2 activity cannot be explained by a simple transition to an activated conformational state with enhanced active site accessibility. Manipulation of solvent viscosity highlighted an unusual bi-phasic behavior of the enzymatic activity, which together with MD calculations supports the importance of motion in the regulation of the activity of HtrA2. HtrA2 is an unusually thermostable enzyme (TM=97.3 degrees C), a trait often associated with structural rigidity, not dynamic motion. We suggest that this thermostability functions to provide a stable scaffold for the observed loop motions, allowing them a relatively free conformational search within a rather restricted volume.

Molecular motion regulates the activity of the Mitochondrial Serine Protease HtrA2.,Merski M, Moreira C, Abreu RM, Ramos MJ, Fernandes PA, Martins LM, Pereira PJB, Macedo-Ribeiro S Cell Death Dis. 2017 Oct 12;8(10):e3119. doi: 10.1038/cddis.2017.487. PMID:29022916^[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
↑ Merski M, Moreira C, Abreu RM, Ramos MJ, Fernandes PA, Martins LM, Pereira PJB, Macedo-Ribeiro S. Molecular motion regulates the activity of the Mitochondrial Serine Protease HtrA2. Cell Death Dis. 2017 Oct 12;8(10):e3119. doi: 10.1038/cddis.2017.487. PMID:29022916 doi:http://dx.doi.org/10.1038/cddis.2017.487

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/5to0"

@@ Line 1: / Line 1: @@
 ==HTRA2 S276C mutant==
-<StructureSection load='5to0' size='340' side='right' caption='[[5to0]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
+<StructureSection load='5to0' size='340' side='right'caption='[[5to0]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5to0]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TO0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TO0 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5to0]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TO0 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5TO0 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5m3n|5m3n]], [[5m3o|5m3o]], [[5tnz|5tnz]], [[5tny|5tny]], [[5to1|5to1]]</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=5to0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5to0 OCA], [http://pdbe.org/5to0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5to0 RCSB], [http://www.ebi.ac.uk/pdbsum/5to0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5to0 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=5to0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5to0 OCA], [http://pdbe.org/5to0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5to0 RCSB], [http://www.ebi.ac.uk/pdbsum/5to0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5to0 ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 22: / Line 22: @@
 </div>
 <div class="pdbe-citations 5to0" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Proteinase|Proteinase]]
+*[[Proteinase 3D structures|Proteinase 3D structures]]
 == References ==
 <references/>
@@ Line 27: / Line 31: @@
 </StructureSection>
 [[Category: HtrA2 peptidase]]
+[[Category: Large Structures]]
 [[Category: Macedo-Ribeiro, S]]
 [[Category: Merski, M]]

5to0

From Proteopedia

Revision as of 12:14, 23 September 2020

HTRA2 S276C mutant

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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