Abstract
Superoxide dismutase (SOD) is the primary enzyme of the cellular antioxidant defense cascade. Misfolding, concomitant oligomerization, and higher order aggregation of human cytosolic SOD are linked to amyotrophic lateral sclerosis (ALS). Although, with two metal ion cofactors SOD1 is extremely robust, the de-metallated apo form is intrinsically disordered. Since the rise of oxygen-based metabolism and antioxidant defense systems are evolutionary coupled, SOD is an interesting protein with a deep evolutionary history. We deployed statistical analysis of sequence space to decode evolutionarily co-varying residues in this protein. These were validated by applying graph theoretical modelling to understand the impact of the presence of metal ion co-factors in dictating the disordered (apo) to hidden disordered (wild-type SOD1) transition. Contact maps were generated for different variants, and the selected significant residues were mapped on separate structure networks. Sequence space analysis coupled with structure networks helped us to map the evolutionarily coupled co-varying patches in the SOD1 and its metal-depleted variants. In addition, using structure network analysis, the residues with a major impact on the internal dynamics of the protein structure were investigated. Our results reveal that the bulk of these evolutionarily co-varying residues are localized in the loop regions and positioned differentially depending upon the metal residence and concomitant steric restrictions of the loops.
Highlights
In order to explore how one position of the protein co-varies with other positions from an evolutionary perspective, direct coupling analysis (DCA) was implemented on the MSalign to retrieve highly co-varying coupled pairs
The coupling study revealed positional correlations of residues; depending upon the impact of whole sequence, we obtained MIcij that corresponded to the mutual information (MI) scores and, by disentangling indirect interactions from the direct ones, DIcij was generated that specifies the direct information (DI) scores
Scores, a probable set of interacting partners were obtained (Figure 1A,B), among which top MI and DI pairs imposing contacts are listed in Tables 2 and 3 respectively
Summary
They are crafted to perform a defined function which gives them their biological relevance [1]. Superoxide dismutase is of immense importance from an evolutionary standpoint, since it had its Biomolecules 2019, 9, 826; doi:10.3390/biom9120826 www.mdpi.com/journal/biomolecules. Biomolecules 2019, 9, 826 origin at a significant geo-biological transition, the Great Oxidation Era. Biomolecules 2019, 9, 826 origin at a significant geo-biological transition, the Great Oxidation Era This geological era witnessed the rise and dominance of cyano-bacterial life forms which, in turn, was responsible for enriching the. The inundation of Earth’s atmosphere with molecular oxygen was coupled with the rise of oxygen-based metabolism and, oxygen-based life forms [2]
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