All-atom Langevin dynamics simulations have been performed to study the folding pathways of the 18-residue binding domain fragment E6ap of the human papillomavirus E6 interacting peptide. Six independent folding trajectories, with a total duration of nearly 2 micros, all lead to the same native state in which the E6ap adopts a fluctuating alpha-helix structure in the central portion (Ser-4-Leu-...

As a consequence of the rugged landscape of RNA molecules their folding is described by the kinetic partitioning mechanism according to which only a small fraction (φF) reaches the folded state while the remaining fraction of molecules is kinetically trapped in misfolded intermediates. The transition from the misfolded states to the native state can far exceed biologically relevant time. Thus, ...

Global folding of polypeptides entering the endoplasmic reticulum (ER) starts as soon as they emerge from the narrow Sec61 translocon. Attainment of the native structure can take from several minutes to hours, depending on the gene product. Until then, non-native folding intermediates must be protected from molecular chaperones that recognize misfolded determinants and could prematurely interru...

Mutations in collagen II are associated with spondyloepiphyseal dysplasia, a group of heritable diseases whose common features include aberrations of skeletal growth. The mechanisms through which mutations in collagen II affect the cartilaginous tissues are complex and include both intracellular and extracellular processes. One of those mechanisms involves cellular stress caused by excessive ac...

Propagation of transmissible spongiform encephalopathies is associated with the conversion of normal prion protein, PrP(C), into a misfolded, oligomeric form, PrP(Sc). Although the high-resolution structure of the PrP(C) is well characterized, the structural properties of PrP(Sc) remain elusive. Here we used MS analysis of H/D backbone amide exchange to examine the structure of amyloid fibrils ...

Protein quality control (PQC) degradation protects the cell by preventing the toxic accumulation of misfolded proteins. In eukaryotes, PQC degradation is primarily achieved by ubiquitin ligases that attach ubiquitin to misfolded proteins for proteasome degradation. To function effectively, PQC ubiquitin ligases must distinguish misfolded proteins from their normal counterparts by recognizing an...

Gram-negative bacteria respond to misfolded proteins in the cell envelope with the sigmaE-driven expression of periplasmic proteases/chaperones. Activation of sigmaE is controlled by a proteolytic cascade that is initiated by the DegS protease. DegS senses misfolded protein in the periplasm, undergoes autoactivation, and cleaves the antisigma factor RseA. Here, we present the crystal structures...