Electron Transfer Interactome of Cytochrome c

Abstract

Lying at the heart of many vital cellular processes such as photosynthesis and respiration, biological electron transfer (ET) is mediated by transient interactions among proteins that recognize multiple binding partners. Accurate description of the ET complexes – necessary for a comprehensive understanding of the cellular signaling and metabolism – is compounded by their short lifetimes and pronounced binding promiscuity. Here, we used a computational approach relying solely on the steric properties of the individual proteins to predict the ET properties of protein complexes constituting the functional interactome of the eukaryotic cytochrome c (Cc). Cc is a small, soluble, highly-conserved electron carrier protein that coordinates the electron flow among different redox partners. In eukaryotes, Cc is a key component of the mitochondrial respiratory chain, where it shuttles electrons between its reductase and oxidase, and an essential electron donor or acceptor in a number of other redox systems. Starting from the structures of individual proteins, we performed extensive conformational sampling of the ET-competent binding geometries, which allowed mapping out functional epitopes in the Cc complexes, estimating the upper limit of the ET rate in a given system, assessing ET properties of different binding stoichiometries, and gauging the effect of domain mobility on the intermolecular ET. The resulting picture of the Cc interactome 1) reveals that most ET-competent binding geometries are located in electrostatically favorable regions, 2) indicates that the ET can take place from more than one protein-protein orientation, and 3) suggests that protein dynamics within redox complexes, and not the electron tunneling event itself, is the rate-limiting step in the intermolecular ET. Further, we show that the functional epitope size correlates with the extent of dynamics in the Cc complexes and thus can be used as a diagnostic tool for protein mobility.

Gregory S. Ezra

“…The communication maps reveal that Trp59 lies along an energy transport pathway that emerges from the heme side chains, consistent with the picosecond response time to excitation of the heme observed in the UVRR experiments [26]. However, the energy transport pathways in cytochrome c, like those for electron transfer [82], could be altered when this protein interacts with its cellular environment. However, the energy transport pathways in cytochrome c, like those for electron transfer [82], could be altered when this protein interacts with its cellular environment.…”

“…. Here, we use the normalization procedure due to Dragt and Finn [ 82 ], which is classifi ed as format 2a in [ 12 ]. , q n ) be coordinates in an n -dimensional Hamiltonian system and p = (p 1 , .…”

Correlation between the potency of flavonoids for cytochrome c reduction and inhibition of cardiolipin‐induced peroxidase activity

“…Indeed, molecular docking simulations have suggested that flavonoids can interact with Cyt c at different sites or in different modes, but all of them share binding to basic residues, namely, Lys79, Arg38, Lys39, Lys13 and His18, consistent with the importance of electrostatic forces and pH in the reduction of Cyt c . Moreover, interaction of flavonoids with Lys79 and vicinal basic residues of Cyt c may further potentiate electronic capture by the heme , which could explain the high reducing efficiency of flavonoids like quercetin, kaempferol and cyanidin. Furthermore, a cluster of Lys and His residues at the entrance of the heme crevice constitutes the L site implicated in Cyt c interaction with acidic lipids, with p K a values 6.5–7 , which correlates with the pH‐dependence of the reduction rates by quercetin and kaempferol found in our work.…”

Adsorption characteristics of Cytochrome c/DNA complex Langmuir molecular assemblies at the air–water interface: a surface area-normalized isotherm study

“…26 Isoelectric point (pI) of Cyt c is 10.02-10.5 and the abundant charged lysine residues around the heme edge 27 is responsible for rapid interprotein electron transfer due to electrostatic steering. 28 Cyt c at neutral pH has a net positively charge causing its stickiness and this also facilitates some strong and unspecic interactions. 29 It can act as surfactant in reverse micellar solution.…”