Computational and Experimental Insights in Redox-Coupled Proton Pumping in Proteins

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(A,B) Structure of the full membrane domain of complex I and only the Nqo4 subunit of the periplasmic domain from T. thermophilus [PDB ID: 4HEA (Baradaran et al., 2013)] highlighting proton transfer paths. (A) Residues that have been proposed to be important for proton pumping are shown as sticks and labeled as subunit number (one letter amino acid designation-residue number). Quinone is yellow and N2 of each Iron Sulfur cluster is green. Approximate locations of putative proton transfer paths are blue arrows and dashed lines show alternative, proposed paths. (B) Residues that are included in the conservation analysis. Purple sticks: E channel cluster in the center of the protein [Cluster 4 in (Khaniya et al., 2020)]; Sticks colored by atom type: antiporter residues (Baradaran et al., 2013; Di Luca et al., 2017; Haapanen and Sharma, 2017; Gutiérrez-Fernández et al., 2020). (C,D) Conservation analysis shown as Weblogo (Crooks, 2004) representation of multiple sequence alignment of 1,000 complex I sequences (Johnson et al., 2008; Sievers et al., 2011). (C) Residues in the three linear antiporter pathways in Nqo12 (Top), Nqo13 (Middle) and Nqo14 (Bottom) subunits. (D) Residues in the E-channel cluster 4. Residues from Nqo8 (Top), Nqo7 (Middle) and Nqo10 (Bottom).
Review
15 June 2021
Protein Motifs for Proton Transfers That Build the Transmembrane Proton Gradient
Divya Kaur
2 more and 
M. R. Gunner

Biological membranes are barriers to polar molecules, so membrane embedded proteins control the transfers between cellular compartments. Protein controlled transport moves substrates and activates cellular signaling cascades. In addition, the electrochemical gradient across mitochondrial, bacterial and chloroplast membranes, is a key source of stored cellular energy. This is generated by electron, proton and ion transfers through proteins. The gradient is used to fuel ATP synthesis and to drive active transport. Here the mechanisms by which protons move into the buried active sites of Photosystem II (PSII), bacterial RCs (bRCs) and through the proton pumps, Bacteriorhodopsin (bR), Complex I and Cytochrome c oxidase (CcO), are reviewed. These proteins all use water filled proton transfer paths. The proton pumps, that move protons uphill from low to high concentration compartments, also utilize Proton Loading Sites (PLS), that transiently load and unload protons and gates, which block backflow of protons. PLS and gates should be synchronized so PLS proton affinity is high when the gate opens to the side with few protons and low when the path is open to the high concentration side. Proton transfer paths in the proteins we describe have different design features. Linear paths are seen with a unique entry and exit and a relatively straight path between them. Alternatively, paths can be complex with a tangle of possible routes. Likewise, PLS can be a single residue that changes protonation state or a cluster of residues with multiple charge and tautomer states.

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Review
30 April 2021

NADH: ubiquinone oxidoreductase (complex I) is the first enzyme complex of the respiratory chain. Complex I is a redox-driven proton pump that contributes to the proton motive force that drives ATP synthase. The structure of complex I has been analyzed by x-ray crystallography and electron cryo-microscopy and is now well-described. The ubiquinone (Q) reduction site of complex I is buried in the peripheral arm and a tunnel-like structure is thought to provide access for the hydrophobic substrate from the membrane. Several intermediate binding positions for Q in the tunnel were identified in molecular simulations. Structural data showed the binding of native Q molecules and short chain analogs and inhibitors in the access pathway and in the Q reduction site, respectively. We here review the current knowledge on the interaction of complex I with Q and discuss recent hypothetical models for the coupling mechanism.

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3,054 views
20 citations
Distribution of NrfD-like subunits in Prokaryotes. The diagram indicates the percentage of the species within each phylum containing at least one gene encoding a NrfD-like subunit. The color code is indicated in the figure.
Original Research
13 April 2021

Several energy-transducing microbial enzymes have their peripheral subunits connected to the membrane through an integral membrane protein, that interacts with quinones but does not have redox cofactors, the so-called NrfD-like subunit. The periplasmic nitrite reductase (NrfABCD) was the first complex recognized to have a membrane subunit with these characteristics and consequently provided the family's name: NrfD. Sequence analyses indicate that NrfD homologs are present in many diverse enzymes, such as polysulfide reductase (PsrABC), respiratory alternative complex III (ACIII), dimethyl sulfoxide (DMSO) reductase (DmsABC), tetrathionate reductase (TtrABC), sulfur reductase complex (SreABC), sulfite dehydrogenase (SoeABC), quinone reductase complex (QrcABCD), nine-heme cytochrome complex (NhcABCD), group-2 [NiFe] hydrogenase (Hyd-2), dissimilatory sulfite-reductase complex (DsrMKJOP), arsenate reductase (ArrC) and multiheme cytochrome c sulfite reductase (MccACD). The molecular structure of ACIII subunit C (ActC) and Psr subunit C (PsrC), NrfD-like subunits, revealed the existence of ion-conducting pathways. We performed thorough primary structural analyses and built structural models of the NrfD-like subunits. We observed that all these subunits are constituted by two structural repeats composed of four-helix bundles, possibly harboring ion-conducting pathways and containing a quinone/quinol binding site. NrfD-like subunits may be the ion-pumping module of several enzymes. Our data impact on the discussion of functional implications of the NrfD-like subunit-containing complexes, namely in their ability to transduce energy.

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