| Structural highlights
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.
See Also
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
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