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Pressure Adaptations in Deep-Sea Moritella Dihydrofolate Reductases: Compressibility versus Stability.

ABSTRACT: Proteins from "pressure-loving" piezophiles appear to adapt by greater compressibility via larger total cavity volume. However, larger cavities in proteins have been associated with lower unfolding pressures. Here, dihydrofolate reductase (DHFR) from a moderate piezophile Moritella profunda (Mp) isolated at ~2.9 km in depth and from a hyperpiezophile Moritella yayanosii (My) isolated at ~11 km in depth were compared using molecular dynamics simulations. Although previous simulations indicate that MpDHFR is more compressible than a mesophile DHFR, here the average properties and a quasiharmonic analysis indicate that MpDHFR and MyDHFR have similar compressibilities. A cavity analysis also indicates that the three unique mutations in MyDHFR are near cavities, although the cavities are generally similar in size in both. However, while a cleft overlaps an internal cavity, thus forming a pathway from the surface to the interior in MpDHFR, the unique residue Tyr103 found in MyDHFR forms a hydrogen bond with Leu78, and the sidechain separates the cleft from the cavity. Thus, while Moritella DHFR may generally be well suited to high-pressure environments because of their greater compressibility, adaptation for greater depths may be to prevent water entry into the interior cavities.

SUBMITTER: Penhallurick RW

PROVIDER: S-EPMC8614765 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Dimethyl sulfoxide (DMSO) acts as a substantial sink for dimethyl sulfide (DMS) in deep waters and is therefore considered a potential electron acceptor supporting abyssal ecosystems. Shewanella piezotolerans WP3 was isolated from west Pacific deep-sea sediments, and two functional DMSO respiratory subsystems are essential for maximum growth of WP3 under in situ conditions (4°C/20 MPa). However, the relationship between these two subsystems and the electron transport pathway underlying DMSO reduction by WP3 remain unknown. In this study, both DMSO reductases (type I and type VI) in WP3 were found to be functionally independent despite their close evolutionary relationship. Moreover, immunogold labeling of DMSO reductase subunits revealed that the type I DMSO reductase was localized on the outer leaflet of the outer membrane, whereas the type VI DMSO reductase was located within the periplasmic space. CymA, a cytoplasmic membrane-bound tetraheme c-type cytochrome, served as a preferential electron transport protein for the type I and type VI DMSO reductases, in which type VI accepted electrons from CymA in a DmsE- and DmsF-independent manner. Based on these results, we proposed a core electron transport model of DMSO reduction in the deep-sea bacterium S. piezotolerans WP3. These results collectively suggest that the possession of two sets of DMSO reductases with distinct subcellular localizations may be an adaptive strategy for WP3 to achieve maximum DMSO utilization in deep-sea environments.IMPORTANCE As the dominant methylated sulfur compound in deep oceanic water, dimethyl sulfoxide (DMSO) has been suggested to play an important role in the marine biogeochemical cycle of the volatile anti-greenhouse gas dimethyl sulfide (DMS). Two sets of DMSO respiratory systems in the deep-sea bacterium Shewanella piezotolerans WP3 have previously been identified to mediate DMSO reduction under in situ conditions (4°C/20 MPa). Here, we report that the two DMSO reductases (type I and type VI) in WP3 have distinct subcellular localizations, in which type I DMSO reductase is localized to the exterior surface of the outer membrane and type VI DMSO reductase resides in the periplasmic space. A core electron transport model of DMSO reduction in WP3 was constructed based on genetic and physiological data. These results will contribute to a comprehensive understanding of the adaptation mechanisms of anaerobic respiratory systems in benthic microorganisms.

Project description:BACKGROUND:Plasmodium falciparum readily develops resistance to the anti-folates pyrimethamine and proguanil via a characteristic set of mutations in the dihydrofolate reductase (PfDHFR) gene that leads to reduced competitive drug binding at the enzyme's active site. Analogous mutations can be found in the DHFR gene in isolates of Plasmodium vivax (PvDHFR) although anti-folates have not been widely used for the treatment of this infection. Here the interactions between DHFR inhibitors and modelled structures of the DHFR enzymes of Plasmodium malariae (PmDHFR) and Plasmodium ovale (PoDHFR) are described, along with an investigation of the effect of recently reported mutations within PmDHFR. METHODS:DHFR models for PmDHFR and PoDHFR were constructed using the solved PfDHFR-TS and PvDHFR structures respectively as templates. The modelled structures were docked with three DHFR inhibitors as ligands and more detailed interactions were explored via simulation of molecular dynamics. RESULTS:Highly accurate models were obtained containing sets of residues that mediate ligand binding which are highly comparable to those mediating binding in known crystal structures. Within this set, there were differences in the relative contribution of individual residues to inhibitor binding. Modelling of PmDHFR mutant sequences revealed that PmDHFR I170M was associated with a significant reduction in binding energy to all DHFR inhibitors studied, while the other predicted resistance mutations had lesser or no effects on ligand binding. CONCLUSIONS:Binding of DHFR inhibitors to the active sites of all four Plasmodium enzymes is broadly similar, being determined by an analogous set of seven residues. PmDHFR mutations found in field isolates influenced inhibitor interactions to a varying extent. In the case of the isolated I170M mutation, the loss of interaction with pyrimethamine suggests that DHFR-inhibitor interactions in P. malariae are different to those seen for DHFRs from P. falciparum and P. vivax.

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Pressure Adaptations in Deep-Sea Moritella Dihydrofolate Reductases: Compressibility versus Stability.

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