In the cytochrome bc1 complex, the swivel motion of the ironsulfur protein (ISP) between two redox sites constitutes a key component of the mechanism that achieves the separation of the two electrons in a substrate molecule at the quinol oxidation (Qo) site. The question remaining is how the motion of ISP is controlled so that only one electron enters the thermodynamically favorable chain via ISP. An analysis of eight structures of mitochondrial bc1 with bound Qo site inhibitors revealed that the presence of inhibitors causes a bidirectional repositioning of the cd1 helix in the cytochrome b subunit. As the cd1 helix forms a major part of the ISP binding crater, any positional shift of this helix modulates the ability of cytochrome b to bind ISP. The analysis also suggests a mechanism for reversal of the ISP fixation when the shape complementarity is significantly reduced after a positional reorientation of the reaction product quinone. The importance of shape complementarity in this mechanism was confirmed by functional studies of bc1 mutants and by a structure determination of the bacterial form of bc1. A mechanism for the high fidelity of the bifurcated electron transfer is proposed.crystal structures ͉ electron transfer ͉ inhibitor binding ͉ mechanism W ithin cellular energy-conserving membranes (the mitochondrial inner membrane in eukaryotes and the plasma membrane in prokaryotes), the only mobile carriers of redox equivalents are ubiquinone (Q), ubiquinol (QH 2 ), and their derivatives. In the cytochrome (cyt) bc 1 complex (cyt bc 1 or bc 1 ) of the respiratory chain, QH 2 is oxidized to Q, and concomitantly, protons are pumped against the gradient across the membrane [from the matrix to the intermembrane space (IMS) in mitochondria and from the cytoplasm to the periplasm in prokaryotes], thus contributing to the electrochemical potential that drives ATP synthesis. The proposed mechanism by which bc 1 performs this dual task, the Q-cycle hypothesis (1), has been widely accepted; it suggests that for the oxidation of two molecules of QH 2 , one molecule of Q is reduced at separate catalytic sites (Fig. 1A). According to this mechanism, the Q reduction site is located near the negative side of the membrane (Q i ͞Q n , the mitochondrial matrix or cytoplasmic side) and is electronically linked via two prosthetic groups [high-potential b heme (b H ) and low-potential b heme (b L )] to the quinol oxidation site located close to the positive side of the membrane (Q o ͞Q p , the mitochondrial IMS side or periplasmic side in prokaryotes). At the Q o site, one electron from a substrate enters the energetically favorable path that leads via the iron-sulfur protein (ISP) and cyt c 1 subunit (cyt c 1 ) to the substrate cyt c, whereas the other electron proceeds via the b L and b H heme groups to Q (or semiquinone) bound at the Q i site. The half-reduction of a Q per oxidized quinol is achieved by the bifurcation of the electron pathway at the Q o site. In a complete catalytic cycle, two protons are taken up from the ma...

Previous studies of traditional and modern value orientations in individuals found mediated predictive relationships of these values on particular mental disorders. The aim of this study with samples from three countries (Germany, Russia, and China) is to extend findings on mental health (MH) and value orientations to broader MH indicators and two types of mediators, i.e. social support and resilience in accordance to a theory of values and modernization/postmodernization. The multisite study was conducted in the three countries. A path-model with traditional values predicting MH mediated by social support, and modern values predicting MH mediated by resilience was tested in all three countries. As expected, value orientations were for the most part strongest in China, followed by Russia and Germany. Structural equation modeling supported the assumption of mediated prediction of MH by value orientations by and large. The traditional value benevolence predicts social support whereas the modern value self-direction predicts resilience. Value orientations are a sensitive tool to empirically describe cross-cultural differences. The findings indicate that personal value orientations are meaningful predictors of MH. The analysis of personal values shows promise in linking public health, cross-cultural and modernization issues.

Papaya Mosaic Virus (PapMV) is a filamentous plant virus that belongs to the Alphaflexiviridae family. Flexible filamentous viruses have defied more than two decades of effort in fiber diffraction, and no high-resolution structure is available for any member of the Alphaflexiviridae family. Here we report our structural characterization of PapMV by X-ray crystallography and cryo-EM 3D reconstruction. We found that PapMV is 135 Å in diameter with a helical symmetry of ~ 10 subunits per turn. Crystal structure of the C-terminal truncated PMV coat protein reveals a novel all helix fold with seven α-helices. Thus the PMV CP structure is different from the four-helix bundle fold of Tobacco Mosaic Virus (TMV) in which helix bundling dominates the subunit interface in TMV and conveys rigidity to the rod virus. PapMV coat protein was crystallized as an asymmetrical dimer in which one protein lassoes the other by the N-terminal peptide. Mutation of residues critical to the inter-subunit lasso interaction abolishes coat protein polymerization. The crystal structure suggests that PMV may polymerize via the consecutive N-terminal loop lassoing mechanism. The structure of PapMV will be useful for rational design and engineering of the PapMV nanoparticles into innovative vaccines.

Vacuolar ATPases (V-ATPases) play a critical role in regulating extracellular acidification of osteoclasts and bone resorption. The deficiencies of subunit a3 and d2 of V-ATPases result in increased bone density in humans and mice. One of the traditional drug design strategies in treating osteoporosis is the use of subunit a3 inhibitor. Recent findings connect subunits H and G1 with decreased bone density. Given the controversial effects of ATPase subunits on bone density, there is a critical need to review the subunits of V-ATPase in osteoclasts and their functions in regulating osteoclasts and bone remodeling. In this review, we comprehensively address the following areas: information about all V-ATPase subunits and their isoforms; summary of V-ATPase subunits associated with human genetic diseases; V-ATPase subunits and osteopetrosis/osteoporosis; screening of all V-ATPase subunits variants in GEFOS data and in-house data; spectrum of V-ATPase subunits during osteoclastogenesis; direct and indirect roles of subunits of V-ATPases in osteoclasts; V-ATPase-associated signaling pathways in osteoclasts; interactions among V-ATPase subunits in osteoclasts; osteoclast-specific V-ATPase inhibitors; perspective of future inhibitors or activators targeting V-ATPase subunits in the treatment of osteoporosis.

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