5wyn

From Proteopedia

(Difference between revisions)

Revision as of 07:51, 29 August 2018

HtrA2 Pathogenic Mutant

Structural highlights

5wyn 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

Serine protease HtrA2 (High temperature requirement protease A2), is involved in apoptosis and protein quality control. However, one of its murine inactive mutants, (S276C aka mnd2) is associated with motor neuron degeneration 2. Similarly, this conserved mutation in human HtrA2 (hHtrA2) also renders the protease inactive, implicating pathogenicity. However, the structural determinants for its inactivation have not yet been elucidated. Here, using multidisciplinary approach, we studied the structural basis of inactivity associated with this mutation in hHtrA2. Characterization of secondary and tertiary structural properties, protein stability, oligomeric properties and enzyme activity for both wild type and mutant has been performed using biophysical and functional enzymology studies. The structural comparison at atomic resolution has been carried out using X-ray crystallography. While enzyme kinetics showed inactivity, spectroscopic probes did not identify any significant secondary structural changes in the mutant. X-ray crystallographic analysis of the mutant protein at 2A resolution highlighted the significance of a water molecule that plays important role in mediating intermolecular interactions for maintaining the functional ensemble of the protease. Overall, the crystallographic data, along with biophysical and enzymology studies helped decipher the structural basis of inactivity of hHtrA2S276C, which might pave way toward further investigating its correlation with aberration of normal cellular functions, hence pathogenicity.

Structural Basis of Inactivation of Human Counterpart of Mouse Motor Neuron Degeneration 2 Mutant in Serine Protease HtrA2.,Wagh AR, Bose K Biosci Rep. 2018 Aug 1. pii: BSR20181072. doi: 10.1042/BSR20181072. PMID:30068699^[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
↑ Wagh AR, Bose K. Structural Basis of Inactivation of Human Counterpart of Mouse Motor Neuron Degeneration 2 Mutant in Serine Protease HtrA2. Biosci Rep. 2018 Aug 1. pii: BSR20181072. doi: 10.1042/BSR20181072. PMID:30068699 doi:http://dx.doi.org/10.1042/BSR20181072

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

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

@@ Line 3: / Line 3: @@
 <StructureSection load='5wyn' size='340' side='right' caption='[[5wyn]], [[Resolution|resolution]] 2.05&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5wyn]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WYN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WYN FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5wyn]] 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=5WYN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WYN 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=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</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=5wyn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wyn OCA], [http://pdbe.org/5wyn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wyn RCSB], [http://www.ebi.ac.uk/pdbsum/5wyn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wyn ProSAT]</span></td></tr>
@@ Line 12: / Line 13: @@
 == Function ==
 [[http://www.uniprot.org/uniprot/HTRA2_HUMAN 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.<ref>PMID:15200957</ref> <ref>PMID:19502560</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Serine protease HtrA2 (High temperature requirement protease A2), is involved in apoptosis and protein quality control. However, one of its murine inactive mutants, (S276C aka mnd2) is associated with motor neuron degeneration 2. Similarly, this conserved mutation in human HtrA2 (hHtrA2) also renders the protease inactive, implicating pathogenicity. However, the structural determinants for its inactivation have not yet been elucidated. Here, using multidisciplinary approach, we studied the structural basis of inactivity associated with this mutation in hHtrA2. Characterization of secondary and tertiary structural properties, protein stability, oligomeric properties and enzyme activity for both wild type and mutant has been performed using biophysical and functional enzymology studies. The structural comparison at atomic resolution has been carried out using X-ray crystallography. While enzyme kinetics showed inactivity, spectroscopic probes did not identify any significant secondary structural changes in the mutant. X-ray crystallographic analysis of the mutant protein at 2A resolution highlighted the significance of a water molecule that plays important role in mediating intermolecular interactions for maintaining the functional ensemble of the protease. Overall, the crystallographic data, along with biophysical and enzymology studies helped decipher the structural basis of inactivity of hHtrA2S276C, which might pave way toward further investigating its correlation with aberration of normal cellular functions, hence pathogenicity.
+Structural Basis of Inactivation of Human Counterpart of Mouse Motor Neuron Degeneration 2 Mutant in Serine Protease HtrA2.,Wagh AR, Bose K Biosci Rep. 2018 Aug 1. pii: BSR20181072. doi: 10.1042/BSR20181072. PMID:30068699<ref>PMID:30068699</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 5wyn" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
@@ Line 17: / Line 27: @@
 </StructureSection>
 [[Category: HtrA2 peptidase]]
+[[Category: Human]]
 [[Category: Bose, K]]
 [[Category: Wagh, A R]]

5wyn

From Proteopedia

Revision as of 07:51, 29 August 2018

HtrA2 Pathogenic Mutant

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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