Mechanisms of mono- and poly-ubiquitination: Ubiquitination specificity depends on compatibility between the E2 catalytic core and amino acid residues proximal to the lysine

Ubiquitination involves the attachment of ubiquitin to lysine residues on substrate proteins or itself, which can result in protein monoubiquitination or polyubiquitination. Ubiquitin attachment to different lysine residues can generate diverse substrate-ubiquitin structures, targeting proteins to different fates. The mechanisms of lysine selection are not well understood. Ubiquitination by the largest group of E3 ligases, the RING-family E3 s, is catalyzed through co-operation between the non-catalytic ubiquitin-ligase (E3) and the ubiquitin-conjugating enzyme (E2), where the RING E3 binds the substrate and the E2 catalyzes ubiquitin transfer. Previous studies suggest that ubiquitination sites are selected by E3-mediated positioning of the lysine toward the E2 active site. Ultimately, at a catalytic level, ubiquitination of lysine residues within the substrate or ubiquitin occurs by nucleophilic attack of the lysine residue on the thioester bond linking the E2 catalytic cysteine to ubiquitin. One of the best studied RING E3/E2 complexes is the Skp1/Cul1/F box protein complex, SCFCdc4, and its cognate E2, Cdc34, which target the CDK inhibitor Sic1 for K48-linked polyubiquitination, leading to its proteasomal degradation. Our recent studies of this model system demonstrated that residues surrounding Sic1 lysines or lysine 48 in ubiquitin are critical for ubiquitination. This sequence-dependence is linked to evolutionarily conserved key residues in the catalytic region of Cdc34 and can determine if Sic1 is mono- or poly-ubiquitinated. Our studies indicate that amino acid determinants in the Cdc34 catalytic region and their compatibility to those surrounding acceptor lysine residues play important roles in lysine selection. This may represent a general mechanism in directing the mode of ubiquitination in E2 s

Vertrauen: Voraussetzung oder Ergebnis effizienter Arbeitsbeziehungen? - Gutenbergs Solidaritätsaxiom und die institutionenökonomische Unternehmenstheorie

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Practical approach to IP Scheduled throughput measurements in Dual Connectivity systems

IP scheduled throughput defined according to 3GPP TS 36.314 reflects user throughput regardless of traffic characteristics, and therefore has become one of the most important indicators for monitoring Quality of Service (QoS) of the end user in Evolved Universal Terrestrial Radio Access Network (E-UTRAN). However, networks built on a distributed architecture make the above definition impossible to be applied directly due to the implementation challenges. This paper gives an overview of the classical Long Term Evolution (LTE) architecture as opposed to Dual Connectivity (DC) topology and focuses on a novel method of solving the calculation issue with the IP scheduled throughput measurement in edge computing environment. Experimental results show a good agreement with the real end user perception

The role of the yeast cleavage and polyadenylation factor subunit Ydh1p/Cft2p in pre‐mRNA 3′‐end formation

Cleavage and polyadenylation factor (CPF) is a multi‐protein complex that functions in pre‐mRNA 3′‐end formation and in the RNA polymerase II (RNAP II) transcription cycle. Ydh1p/Cft2p is an essential component of CPF but its precise role in 3′‐end processing remained unclear. We found that mutations in YDH1 inhibited both the cleavage and the polyadenylation steps of the 3′‐end formation reaction in vitro. Recently, we demonstrated that an important function of CPF lies in the recognition of poly(A) site sequences and RNA binding analyses suggesting that Ydh1p/Cft2p interacts with the poly(A) site region. Here we show that mutant ydh1 strains are deficient in the recognition of the ACT1 cleavage site in vivo. The C‐terminal domain (CTD) of RNAP II plays a major role in coupling 3′‐end processing and transcription. We provide evidence that Ydh1p/Cft2p interacts with the CTD of RNAP II, several other subunits of CPF and with Pcf11p, a component of CF IA. We propose that Ydh1p/Cft2p contributes to the formation of important interaction surfaces that mediate the dynamic association of CPF with RNAP II, the recognition of poly(A) site sequences and the assembly of the polyadenylation machinery on the RNA substrat

Die Rolle der Gerichte in den Arbeitsbeziehungen: eine ökonomische Analyse am Beispiel der Arbeitnehmerhaftung

"In der Diskussion um die Verrechtlichung der Arbeitsbeziehungen lenken wir den Blick auf das vermeintlich (zu) arbeitnehmerfreundliche Richterrecht in Deutschland. Aus rechtsökonomischer Perspektive untersuchen wir exemplarisch die Arbeitnehmerhaftung. Sie ist in dieser Sicht effizient geregelt, wenn die Summe der Kosten aus Prävention, Schadenstragung - unter Berücksichtigung verschiedener Risikotragungsfähigkeiten - sowie aus Schadensregulierung minimiert werden. Entscheidungen des Bundesarbeitsgerichts, in denen die Arbeitnehmerhaftung beschränkt wird, lassen sich als Korrektur des Versagens spontaner Verträge in Richtung der theoretisch effizienten Lösung interpretieren. Arbeitnehmerschutz ist hier gleichzeitig effizient - und wir denken, dass es lohnt, die Effizienzproben der rechtsökonomischen Analyse in der wissenschaftlichen und der rechtspolitischen Diskussion auszudehnen." (Autorenreferat)"In the German discussion on the 'juridification' (Verrechtlichung) of the employment relationship, we focus on the role of judge-made law, which is widely considered as (too) worker-friendly. As an example, we investigate the efficiency of court rulings on workers' liability from an economic perspective. Workers' liability is, from this angle, regulated efficiently if the sum of expenditures on preventive activity, of damage costs, corrected for divergent abilities to bear damage compensation, and of transaction costs of regulation, are minimised. Rulings of the Federal Labour Court (Bundesarbeitsgericht), which limit workers' liability, should be interpreted as a correction of contract failure towards the theoretically efficient solution. In this instance, worker protection promotes efficiency. We hold this type of economic analysis of labour law, with its focus on efficiency, to be an approach which is promising for both industrial relations research and policy." (author's abstract

Antioxidant peroxiredoxin 6 protein rescues toxicity due to oxidative stress and cellular hypoxia in vitro, and attenuates prion-related pathology in vivo

Protein misfolding, mitochondrial dysfunction and oxidative stress are common pathomechanisms that underlie neurodegenerative diseases. In prion disease, central to these processes is the post-translational transformation of cellular prion protein (PrPc) to the aberrant conformationally altered isoform; PrPSc. This can trigger oxidative reactions and impair mitochondrial function by increasing levels of peroxynitrite, causing damage through formation of hydroxyl radicals or via nitration of tyrosine residues on proteins. The 6 member Peroxiredoxin (Prdx) family of redox proteins are thought to be critical protectors against oxidative stress via reduction of H2O2, hydroperoxides and peroxynitrite. In our in vitro studies cellular metabolism of SK-N-SH human neuroblastoma cells was significantly decreased in the presence of H2O2 (oxidative stressor) or CoCl2 (cellular hypoxia), but was rescued by treatment with exogenous Prdx6, suggesting that its protective action is in part mediated through a direct action. We also show that CoCl2-induced apoptosis was significantly decreased by treatment with exogenous Prdx6. We proposed a redox regulator role for Prdx6 in regulating and maintaining cellular homeostasis via its ability to control ROS levels that could otherwise accelerate the emergence of prion-related neuropathology. To confirm this, we established prion disease in mice with and without astrocyte-specific antioxidant protein Prdx6, and demonstrated that expression of Prdx6 protein in Prdx6 Tg ME7-animals reduced severity of the behavioural deficit, decreased neuropathology and increased survival time compared to Prdx6 KO ME7-animals. We conclude that antioxidant Prdx6 attenuates prion-related neuropathology, and propose that augmentation of endogenous Prdx6 protein represents an attractive adjunct therapeutic approach for neurodegenerative diseases

Inhomogeneous vortex-state-driven enhancement of superconductivity in nanoengineered ferromagnet-superconductor heterostructures

Thin film heterostructures provide a powerful means to study the antagonism between superconductivity (SC) and ferromagnetism (FM). One interesting issue in FM-SC hybrids which defies the notion of antagonistic orders is the observation of magnetic field induced superconductivity (FIS). Here we show that in systems where the FM domains/islands produce spatial inhomogeneities of the SC order parameter, the FIS can derive significant contribution from different mobilities of the magnetic flux identified by two distinct critical states in the inhomogeneous superconductor. Our experiments on nanoengineered bilayers of ferromagnetic CoPt and superconducting NbN where CoPt/NbN islands are separated by a granular NbN, lend support to this alternative explanation of FIS in certain class of FM-SC hybrids.Comment: 5 figure

Comment on "Mn Interstitial Diffusion in (Ga,Mn)As"

The magnetic and transport properties of (GaMn)As are known to be influenced by postgrowth annealing, and it is generally accepted that these modifications are due to outdiffusion of Mn interstitials. We show that the annealing-induced modifications are strongly accelerated if the treatment is carried out under As capping. This means that the modification rate is not limited by the diffusion process, but rather by the surface trapping of the diffusing species.Comment: 4 pages, 1 figur

Blocking the apoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice

Accumulation of β-amyloid (Aβ) in the brain is essential to Alzheimer’s disease (AD) pathogenesis. Carriers of the apolipoprotein E (APOE) ε4 allele demonstrate greatly increased AD risk and enhanced brain Aβ deposition. In contrast, APOE ε2 allele carries show reduced AD risk, later age of disease onset, and lesser Aβ accumulation. However, it remains elusive whether the apoE2 isoform exerts truly protective effect against Aβ pathology or apoE2 plays deleterious role albeit less pronounced than the apoE4 isoform. Here, we characterized APP(SW)/PS1(dE9)/APOE ε2-TR (APP/E2) and APP(SW)/PS1(dE9)/APOE ε4-TR (APP/E4) mice, with targeted replacement (TR) of the murine Apoe for human ε2 or ε4 alleles, and used these models to investigate effects of pharmacological inhibition of the apoE/Aβ interaction on Aβ deposition and neuritic degeneration. APP/E2 and APP/E4 mice replicate differential effect of human apoE isoforms on Aβ pathology with APP/E4 mice showing a several-fold greater load of Aβ plaques, insoluble brain Aβ levels, Aβ oligomers, and density of neuritic plaques than APP/E2 mice. Furthermore, APP/E4 mice, but not APP/E2 mice, exhibit memory impairment on object recognition and radial arm maze tests. Between the age of 6 and 10 months APP/E2 and APP/E4 mice received treatment with Aβ12-28P, a non-toxic, synthetic peptide homologous to the apoE binding motif within the Aβ sequence, which competitively blocks the apoE/Aβ interaction. In both lines, the treatment significantly reduced brain Aβ accumulation, co-accumulation of apoE within Aβ plaques, and neuritic degeneration, and prevented memory deficit in APP/E4 mice. These results indicate that both apoE2 and apoE4 isoforms contribute to Aβ deposition and future therapies targeting the apoE/Aβ interaction could produce favorable outcome in APOE ε2 and ε4 allele carriers. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40478-014-0075-0) contains supplementary material, which is available to authorized users