Transmissible spongiform encephalopathies (TSE) are fatal neurodegenerative disorders characterized by the conversion of the normal prion protein (PrP(C)) into aggregates of its pathological conformer (PrP(Sc)). The mechanism behind this structural conversion is unclear. We report the identification of disease-related protein structural differences directly within the tissue environment. Utiliz...

Misfolded proteins accumulating in several neurodegenerative diseases (including Alzheimer, Parkinson, and Huntington diseases) can cause aggregation of their native counterparts through a mechanism similar to the infectious prion protein's induction of a pathogenic conformation onto its cellular isoform. Evidence for such a prion-like mechanism has now spread to the main misfolded proteins, SO...

Background: Group I introns are valuable for studying RNA folding and chaperone proteins. Results: A catalytic activity assay was developed and used to demonstrate two prominent phases for Azoarcus ribozyme folding. The slow phase displays hallmarks of a misfolded intermediate. Conclusion: This RNA accumulates a misfolded intermediate and interacts productively with RNA chaperones. Significance...

The primary structure of polypeptides is converted to their final tertiary and quaternary structure by sequential maturation steps, and the endoplasmic reticulum (ER) provides the environment for the polypeptides to attain their proper 3-dimensional architecture. Proteins that misfold or fail to oligomerize with their partners (Chen et al., 1998; Wileman et al., 1990) are quickly degraded, as u...

Barriers to infection act at multiple levels to prevent viruses, bacteria, and parasites from commandeering host cells for their own purposes. An intriguing hypothesis is that if a cell experiences stress, such as that elicited by inflammation, endoplasmic reticulum (ER) expansion, or misfolded proteins, then subcellular barriers will be less effective at preventing viral infection. Here we hav...

We describe our global optimization method called Stochastic Perturbation with Soft Constraints (SPSC), which uses information from known proteins to predict secondary structure, but not in the tertiary structure predictions or in generating the terms of the physics-based energy function. Our approach is also characterized by the use of an all atom energy function that includes a novel hydropho...

Protein quality control is essential for clearing misfolded and aggregated proteins from the cell, and its failure is associated with many neurodegenerative disorders. Here, we identify two genes, ufd-2 and spr-5, that when inactivated, synergistically and robustly suppress neurotoxicity associated with misfolded proteins in Caenorhabditis elegans. Loss of human orthologs ubiquitination factor ...

In order to function properly, newly synthesised proteins must rapidly and efficiently attain their native conformations. If they fail to do so, the cell may be adversely affected due to loss of function or toxic gain of function effects of misfolded polypeptides. Effective quality control mechanisms to recognise and eliminate misfolded proteins are thus critical for cell viability. The primary...

The endoplasmic reticulum (ER) maintains an environment essential for secretory protein folding. Consequently, the premature transport of polypeptides would be harmful to the cell. To avert this scenario, mechanisms collectively termed "ER quality control" prevent the transport of nascent polypeptides until they properly fold. Irreversibly misfolded molecules are sorted for disposal by the ER-a...

Correct folding of proteins is crucial for proper protein, cell, and organ function.1 Mutations and cellular stresses, some of which occur during pathology, can lead to incorrect folding and subsequent loss of protein function. If it goes uncorrected, then this loss of protein function, along with the toxicity associated with the accumulation of misfolded proteins in cells, results in eventual ...