A conformational isoform of the mammalian prion protein (PrP Sc ) is the sole component of the infectious pathogen that causes the prion diseases. We have obtained X-ray fiber diffraction patterns from infectious prions that show cross- diffraction: meridional intensity at 4.8 Å resolution, indicating the presence of  strands running approximately at right angles to the filament axis and characteristic of amyloid structure. Some of the patterns also indicated the presence of a repeating unit along the fiber axis, corresponding to four -strands. We found that recombinant (rec) PrP amyloid differs substantially from highly infectious brainderived prions, both in structure as demonstrated by the diffraction data, and in heterogeneity as shown by electron microscopy. In addition to the strong 4.8 Å meridional reflection, the recPrP amyloid diffraction is characterized by strong equatorial intensity at approximately 10.5 Å, absent from brain-derived prions, and indicating the presence of stacked -sheets. Synthetic prions recovered from transgenic mice inoculated with recPrP amyloid displayed structural characteristics and homogeneity similar to those of naturally occurring prions. The relationship between the structural differences and prion infectivity is uncertain, but might be explained by any of several hypotheses: only a minority of recPrP amyloid possesses a replication-competent conformation, the majority of recPrP amyloid has to undergo a conformational maturation to acquire replication competency, or inhibitory forms of recPrP amyloid interfere with replication during the initial transmission.amyloid ͉ protein ͉ neurodegeneration ͉ PrP ͉ -helix
We propose a novel combinatorial algorithm for efficient generation of Hamiltonian walks and cycles on a cubic lattice, modeling the conformations of lattice toy proteins. Through extensive tests on small lattices (allowing complete enumeration of Hamiltonian paths), we establish that the new algorithm, although not perfect, is a significant improvement over the earlier approach by Ramakrishnan et. al.[1], as it generates the sample of conformations with dramatically reduced statistical bias. Using this method, we examine the fractal properties of typical compact conformations. In accordance with Flory theorem celebrated in polymer physics, chain pieces are found to follow Gaussian statistics on the scale smaller than the globule size. Cross-over to this Gaussian regime is found to happen at the scales which are numerically somewhat larger than previously believed. We further used Alexander and Vassiliev degrees 2 and 3 topological invariants to identify the trivial knots among the Hamiltonian loops. We found that the probability of being knotted increases with loop length much faster than it was previously thought, and that chain pieces are consistently more compact than Gaussian if the global loop topology is that of a trivial knot.
The insolubility of the disease-causing isoform of the prion protein (PrP(Sc)) has prevented studies of its three-dimensional structure at atomic resolution. Electron crystallography of two-dimensional crystals of N-terminally truncated PrP(Sc) (PrP 27-30) and a miniprion (PrP(Sc)106) provided the first insights at intermediate resolution on the molecular architecture of the prion. Here, we report on the structure of PrP 27-30 and PrP(Sc)106 negatively stained with heavy metals. The interactions of the heavy metals with the crystal lattice were governed by tertiary and quaternary structural elements of the protein as well as the charge and size of the heavy metal salts. Staining with molybdate anions revealed three prominent densities near the center of the trimer that forms the unit cell, coinciding with the location of the beta-helix that was proposed for the structure of PrP(Sc). Differential staining also confirmed the location of the internal deletion of PrP(Sc)106 at or near these densities.
We design toy protein mimicking a machine-like function of an enzyme. Using an insight gained by the study of conformation space of compact lattice polymers, we demonstrate the possibility of a large scale conformational rearrangement which occurs (i) without opening a compact state, and (ii) along a linear (one-dimensional) path. We also demonstrate the possibility to extend sequence design method such that it yields a "collective funnel" landscape in which the toy protein (computationally) folds into the valley with rearrangement path at its bottom. Energies of the states along the path can be designed to be about equal, allowing for diffusion along the path. They can also be designed to provide for a significant bias in one certain direction. Together with a toy ligand molecule, our "enzimatic" machine can perform the entire cycle, including conformational relaxation in one direction upon ligand binding and conformational relaxation in the opposite direction upon ligand release. This model, however schematic, should be useful as a test ground for phenomenological theories of machine-like properties of enzymes.
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