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How and when disulfide bonds form in proteins relative to the stage of their folding is a fundamental question in cell biology. Two models describe this relationship: the folded precursor model, in which a nascent structure forms before disulfides do, and the quasi-stochastic model, where disulfides form prior to folding. Here we investigated oxidative folding of three structurally diverse substrates, β2-microglobulin, prolactin, and the disintegrin domain of ADAM metallopeptidase domain 10 (ADAM10), to understand how these mechanisms apply in a cellular context. We used a eukaryotic cell-free translation system in which we could identify disulfide isomers in stalled translation intermediates to characterize the timing of disulfide formation relative to translocation into the endoplasmic reticulum and the presence of non-native disulfides. Our results indicate that in a domain lacking secondary structure, disulfides form before conformational folding through a process prone to nonnative disulfide formation, whereas in proteins with defined secondary structure, native disulfide formation occurs after partial folding. These findings reveal that the nascent protein structure promotes correct disulfide formation during cotranslational folding.

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Hydrogen spillover-based binary (HSBB) catalysts have attracted more and more attention in recent years because of their unique reaction mechanism, different from traditional single-component catalysts. In this paper, using density functional theory for the screening of materials, we find 11 candidates with excellent hydrogen evolution reaction (HER) performance under acidic conditions. Among them, Pt1Ir1-MoS2 has been successfully synthesized and verified through experiment to have exhibited the outstanding catalytic performance as predicted. Detailed analysis of these HSBB catalysts reveals the key role of hydrogen spillover toward efficient water splitting, paving the way for the discovery of widely applicable materials and a feedback loop that delivers materials as designed. Greatly increasing the number of known HSBB catalysts, the current study not only demonstrates the accuracy of our screening of materials but also provides a novel paradigm for accelerating the development of materials and reducing costs.

Folding of proteins entering the mammalian secretory pathway requires the insertion of the correct disulfides. Disulfide formation involves both an oxidative pathway for their insertion and a reductive pathway to remove incorrectly formed disulfides. Reduction of these disulfides is critical for correct folding and degradation of misfolded proteins. Previously, we showed that the reductive pathway is driven by NADPH generated in the cytosol. Here, by reconstituting the pathway using purified proteins and ER microsomal membranes, we demonstrate that the thioredoxin reductase system provides the minimal cytosolic components required for reducing proteins within the ER lumen. In particular, saturation of the pathway and its protease sensitivity demonstrates the requirement for a membrane protein to shuttle electrons from the cytosol to the ER. These results provide compelling evidence for the critical role of the cytosol in regulating ER redox homeostasis ensuring correct protein folding and facilitating the degradation of misfolded ER proteins.

Ni 5 P 4 has received considerable attention recently as a potentially viable substitute for Pt as the cathode material for catalytic water splitting. The current investigation focuses on theoretical understandings of the characteristics of active sites toward water splitting using first-principle calculations. The results indicate that the activity of bridge NiNi sites is highly related on the bond number with neighbors. If the total bond number of NiNi is higher than 14, the sites will exhibit excellent HER performance. For the top P sites, the activity is greatly affected by the position of coplanar atoms besides the bond number. Data of bond length with neighbors can be used to predict the activity of P sites as reviewed by machine learning. Partial density of state (PDOS) analysis of different P sites illustrates that the activity of P sites should form the appropriate bond to localize some 3p orbits of the P atoms. Bond number and position of neighbors are two key parameters for the prediction of the HER activity. Based on the current work, most of the low-energy surfaces of Ni 5 P 4 are active, indicating a good potential of this materials for hydrogen evolution reactions.

Defect engineering plays an important role in improving the performance of catalysts. To clarify the roles of Co and P vacancy in CoP for water splitting, a theoretical study based...