Quality Control System Response to Stochastic Growth of Amyloid Fibrils

We introduce a stochastic model describing aggregation of misfolded proteins and degradation by the protein quality control system in a single cell. In analogy with existing literature, aggregates can grow, nucleate and fragment stochastically. We assume that the quality control system acts as an enzyme that can degrade aggregates at different stages of the growth process, with an efficiency that decreases with the size of the aggregate. We show how this stochastic dynamics, depending on the parameter choice, leads to two qualitatively different behaviors: a homeostatic state, where the quality control system is stable and aggregates of large sizes are not formed, and an oscillatory state, where the quality control system periodically breaks down, allowing for the formation of large aggregates. We discuss how these periodic breakdowns may constitute a mechanism for the sporadic development of neurodegenerative diseases.Comment: 14 pages, 4 figures, submitte

Letter from the Editor

https://deepblue.lib.umich.edu/bitstream/2027.42/143819/1/A12 Letter from the Editor.pd

Development of local government – a key to poverty reduction in rural Africa

"In sub-Saharan Africa some 80% of the poor live in rural areas and derive most of their incomes, whether in kind or in cash, from agriculture; economic development that is based on agriculture and benefits the mass of the population and the building of development-oriented local government structures providing a wide range of services are therefore essential if poverty is to be reduced. Both aspects have been repeatedly overlooked because of erroneous assessments of the employment, economic linkage and value added potential of peasant farming and the disdain in which the development-promoting significance of rural communities is held; since the 1980s international development cooperation has, moreover, increasingly shifted the emphasis in its promotion to physical and social infrastructure and the service sectors, principally in the industrial and urban sphere. At the same time, there has been a growing realization that the task for rural and agricultural development to proceed sustainably and have the effect of reducing poverty will become a complex, cross-sectional one; this can no longer be performed with conventional approaches to development based on project aid; this is equally true of all globally designed action programmes that influence sustainable agricultural and rural development, such as the implementation of Agenda 21, the plan of action to implement the Desertification Convention, the World Food Summit Plan of Action and the implementation of the poverty reduction strategies to achieve the Millennium Development Goals. From these facts, omissions and findings it must be concluded that poverty reduction in all Africa's agricultural countries should be achieved primarily through agriculturally based development, in which local government must play a role in promoting local economic development, coordinating the intersectoral activities and bridging the service gap between national and local level; this can be achieved only by means of gradual political, institutional and fiscal decentralization. As the rural communities will have to bear the main administrative burden of poverty-reducing development in the future, they must be sustainably strengthened with national and international support; a beneficial agricultural policy environment, realignment of international development cooperation and jointly financed and democratically controlled district development funds are prerequisites for broad-based, poverty-oriented rural development." (excerpt

Simulation, Experiment, and Evolution: Understanding Nucleation in Protein S6 Folding

In this study, we explore nucleation and the transition state ensemble of the ribosomal protein S6 using a Monte Carlo Go model in conjunction with restraints from experiment. The results are analyzed in the context of extensive experimental and evolutionary data. The roles of individual residues in the folding nucleus are identified and the order of events in the S6 folding mechanism is explored in detail. Interpretation of our results agrees with, and extends the utility of, experiments that shift f-values by modulating denaturant concentration and presents strong evidence for the realism of the mechanistic details in our Monte Carlo Go model and the structural interpretation of experimental f-values. We also observe plasticity in the contacts of the hydrophobic core that support the specific nucleus. For S6, which binds to RNA and protein after folding, this plasticity may result from the conformational flexibility required to achieve biological function. These results present a theoretical and conceptual picture that is relevant in understanding the mechanism of nucleation in protein folding.Comment: PNAS in pres

Regulation of mammalian CDC6 by CDK phosphorylation and proteasome dependent degradation.

The mammalian cell cycle is regulated by periodic gene transcription, kinase activities and protein degradation. A human cDNA encoding a protein homologous to S. cerevisiae Cdc6p and S. pombe Cdc18 was identified. Mammalian CDC6 is essential for DNA replication, and the obtained data demonstrate that the mammalian CDC6 protein is regulated by several mechanisms. The subcellular localization of mammalian CDC6 is cell cycle regulated controlled by Cyclin A/CDK2 phosphorylation. The CDC6 protein interacts directly with the Cyclin A/CDK2 complex via a Cy-motif in the N-terminal of CDC6 and phosphorylation of hCDC6 results in relocation of hCDC6 from the nucleus to the cytoplasm during S- phase. The protein level of mammalian CDC6 is growth and cell cycle regulated. The CDC6 protein is induced by stimulation of serum starved fibroblasts and the CDC6 protein level remains high throughout S-phase and G2. As cells progress through mitosis the amount of CDC6 protein declines abruptly. Mammalian CDC6 is an unstable protein. The level of CDC6 protein increases in the presence of proteasome inhibitors and, furthermore, poly-ubiquitinated CDC6 was identified in vivo, demonstrating that CDC6 is targeted for degradation by ubiquitination in mammalian cells. The instability of CDC6 was shown to be dependent on the N- terminal region. A peptide sequence with homology to destruction box sequences found in substrates of the anaphase promoting complex was identified in hCDC6 and shown to mediate the degradation of hCDC6 in quiescent cells. These data suggest that the mammalian CDC6 protein is highly regulated. In GO and early G1 accumulation of the mammalian CDC6 protein is prevented by ubiquitin mediated degradation. During S-phase and G2 mammalian CDC6 is retained in the cytoplasm by Cyclin A/CDK2 phosphorylation