Dataset Information

Structural modeling and in silico analysis of human superoxide dismutase 2.

ABSTRACT: Aging in the world population has increased every year. Superoxide dismutase 2 (Mn-SOD or SOD2) protects against oxidative stress, a main factor influencing cellular longevity. Polymorphisms in SOD2 have been associated with the development of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, as well as psychiatric disorders, such as schizophrenia, depression and bipolar disorder. In this study, all of the described natural variants (S10I, A16V, E66V, G76R, I82T and R156W) of SOD2 were subjected to in silico analysis using eight different algorithms: SNPeffect, PolyPhen-2, PhD-SNP, PMUT, SIFT, SNAP, SNPs&GO and nsSNPAnalyzer. This analysis revealed disparate results for a few of the algorithms. The results showed that, from at least one algorithm, each amino acid substitution appears to harmfully affect the protein. Structural theoretical models were created for variants through comparative modelling performed using the MHOLline server (which includes MODELLER and PROCHECK) and ab initio modelling, using the I-Tasser server. The predicted models were evaluated using TM-align, and the results show that the models were constructed with high accuracy. The RMSD values of the modelled mutants indicated likely pathogenicity for all missense mutations. Structural phylogenetic analysis using ConSurf revealed that human SOD2 is highly conserved. As a result, a human-curated database was generated that enables biologists and clinicians to explore SOD2 nsSNPs, including predictions of their effects and visualisation of the alignment of both the wild-type and mutant structures. The database is freely available at http://bioinfogroup.com/database and will be regularly updated.

SUBMITTER: de Carvalho MD

PROVIDER: S-EPMC3681941 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Structural modeling and in silico analysis of human superoxide dismutase 2.

de Carvalho Mariana Dias Castela MD De Mesquita Joelma Freire JF

PloS one 20130613 6

Aging in the world population has increased every year. Superoxide dismutase 2 (Mn-SOD or SOD2) protects against oxidative stress, a main factor influencing cellular longevity. Polymorphisms in SOD2 have been associated with the development of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, as well as psychiatric disorders, such as schizophrenia, depression and bipolar disorder. In this study, all of the described natural variants (S10I, A16V, E66V, G76R, I82T and R156W) ...[more]

PMID: 23785434

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Project description:Background:Characterizing the structure and function of superoxide dismutase (SOD), as an antioxidant enzyme providing opportunities for its application in food supplements. Objectives:In this study, the features of the Manganese-SOD of Lactococcus Lactis (SDLL), subsp. Cremoris MG1363, as probiotic bacteria, were determined on the basis of the computational methods. Materials and Methods:The protein's physicochemical properties and the prediction of its secondary structure were determined via the ProtParam server and the GOR program respectively. Moreover, the 3D structures of the proteins were constructed via the MODELLER on the basis of the homology method and the threading algorithm MUSTER. On the other hand, the structural stability of the models was assayed under the quasi-physiological conditions by the GROMACS program via the GROMOS96 43a1 force field in Linux system. Finally, using the Molecular Docking Studies, the functionality features of the models were predicted through their affinity with the corresponding substrates. Results:The results revealed the physicochemical properties of the SDLL and a 3D model of a chain of the enzyme being similar to the SOD from the Bacillus Subtilis (SDBS). The model of the SDLL was checked for quality control purposes including the Ramachandran plot, the ERRAT and the Verifiy3D. The model was suggestive of the structural stability in quasi-physiological conditions; yet, less than that of the SDBS. Assessing the cause of the instability in the SDLL model was indicative of two unstable regions in the area far from the enzyme's active position, they were considered suitable for mutagenesis. Accordingly, the loop substitution for the corresponding region of SDBS and the deletion of the loop positioned at the C terminal of SDLL resulted in a mutant of SDLL with more stability and appropriate affinity with the corresponding substrate. Conclusion:In general, the study provides a new model of SDLL with certain thermostable features, and a new mutant with suitable stability and functionality on the basis of the direct mutagenesis being used in different applications.

Project description:Over 130 mutations to copper, zinc superoxide dismutase (SOD) are implicated in the selective death of motor neurons found in 25% of patients with familial amyotrophic lateral sclerosis (ALS). Despite their widespread distribution, ALS mutations appear positioned to cause structural and misfolding defects. Such defects decrease SOD's affinity for zinc, and loss of zinc from SOD is sufficient to induce apoptosis in motor neurons in vitro. To examine the importance of the zinc site in the structure and pathogenesis of human SOD, we determined the 2.0-A-resolution crystal structure of a designed zinc-deficient human SOD, in which two zinc-binding ligands have been mutated to hydrogen-bonding serine residues. This structure revealed a 9 degrees twist of the subunits, which opens the SOD dimer interface and represents the largest intersubunit rotational shift observed for a human SOD variant. Furthermore, the electrostatic loop and zinc-binding subloop were partly disordered, the catalytically important Arg143 was rotated away from the active site, and the normally rigid intramolecular Cys57-Cys146 disulfide bridge assumed two conformations. Together, these changes allow small molecules greater access to the catalytic copper, consistent with the observed increased redox activity of zinc-deficient SOD. Moreover, the dimer interface is weakened and the Cys57-Cys146 disulfide is more labile, as demonstrated by the increased aggregation of zinc-deficient SOD in the presence of a thiol reductant. However, equimolar Cu,Zn SOD rapidly forms heterodimers with zinc-deficient SOD (t1/2 approximately 15 min) and prevents aggregation. The stabilization of zinc-deficient SOD as a heterodimer with Cu,Zn SOD may contribute to the dominant inheritance of ALS mutations. These results have general implications for the importance of framework stability on normal metalloenzyme function and specific implications for the role of zinc ion in the fatal neuropathology associated with SOD mutations.

Dataset Information

Structural modeling and in silico analysis of human superoxide dismutase 2.

Publications

Structural modeling and in silico analysis of human superoxide dismutase 2.

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