580 research outputs found
Self-Templated Nucleation in Peptide and Protein aggregation
Peptides and proteins exhibit a common tendency to assemble into highly
ordered fibrillar aggregates, whose formation proceeds in a
nucleation-dependent manner that is often preceded by the formation of
disordered oligomeric assemblies. This process has received much attention
because disordered oligomeric aggregates have been associated with
neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Here
we describe a self-templated nucleation mechanism that determines the
transition between the initial condensation of polypeptide chains into
disordered assemblies and their reordering into fibrillar structures. The
results that we present show that at the molecular level this transition is due
to the ability of polypeptide chains to reorder within oligomers into fibrillar
assemblies whose surfaces act as templates that stabilise the disordered
assemblies.Comment: 4 pages, 3 figure
Statistical properties of contact vectors
We study the statistical properties of contact vectors, a construct to
characterize a protein's structure. The contact vector of an N-residue protein
is a list of N integers n_i, representing the number of residues in contact
with residue i. We study analytically (at mean-field level) and numerically the
amount of structural information contained in a contact vector. Analytical
calculations reveal that a large variance in the contact numbers reduces the
degeneracy of the mapping between contact vectors and structures. Exact
enumeration for lengths up to N=16 on the three dimensional cubic lattice
indicates that the growth rate of number of contact vectors as a function of N
is only 3% less than that for contact maps. In particular, for compact
structures we present numerical evidence that, practically, each contact vector
corresponds to only a handful of structures. We discuss how this information
can be used for better structure prediction.Comment: 20 pages, 6 figure
Information Loss in Coarse Graining of Polymer Configurations via Contact Matrices
Contact matrices provide a coarse grained description of the configuration
omega of a linear chain (polymer or random walk) on Z^n: C_{ij}(omega)=1 when
the distance between the position of the i-th and j-th step are less than or
equal to some distance "a" and C_{ij}(omega)=0 otherwise. We consider models in
which polymers of length N have weights corresponding to simple and
self-avoiding random walks, SRW and SAW, with "a" the minimal permissible
distance. We prove that to leading order in N, the number of matrices equals
the number of walks for SRW, but not for SAW. The coarse grained Shannon
entropies for SRW agree with the fine grained ones for n <= 2, but differs for
n >= 3.Comment: 18 pages, 2 figures, latex2e Main change: the introduction is
rewritten in a less formal way with the main results explained in simple
term
Statistical Properties of Contact Maps
A contact map is a simple representation of the structure of proteins and
other chain-like macromolecules. This representation is quite amenable to
numerical studies of folding. We show that the number of contact maps
corresponding to the possible configurations of a polypeptide chain of N amino
acids, represented by (N-1)-step self avoiding walks on a lattice, grows
exponentially with N for all dimensions D>1. We carry out exact enumerations in
D=2 on the square and triangular lattices for walks of up to 20 steps and
investigate various statistical properties of contact maps corresponding to
such walks. We also study the exact statistics of contact maps generated by
walks on a ladder.Comment: Latex file, 15 pages, 12 eps figures. To appear on Phys. Rev.
Two inbred rat strains contrasting for anxiety-related behaviors show similar levels of defensive responses to cat odor
Rodents are known to display fear-related responses when exposed to the odor of natural predators, such as cats, even when they are totally naĂŻve to these stimuli. Based on that, a behavioral test in which rats are exposed to cat odor has been developed and proposed to model some forms of anxiety. The objective of the present study was thus to compare the LEW (Lewis) and SHR (spontaneously hypertensive rats) inbred rat strains, which display genetic differences in other classical models of anxiety, in the cat odor test. As expected, cat odor produced an increase in fear-related behaviors. However, no clear differences were found between the two strains tested. These results suggest that the type of stress experienced by LEW and SHR strains exposed to cat odor is different from that elicited by exposure to classical models of anxiety such as the elevated plus-maze, black/white box and open-field tests
Protein folding using contact maps
We present the development of the idea to use dynamics in the space of
contact maps as a computational approach to the protein folding problem. We
first introduce two important technical ingredients, the reconstruction of a
three dimensional conformation from a contact map and the Monte Carlo dynamics
in contact map space. We then discuss two approximations to the free energy of
the contact maps and a method to derive energy parameters based on perceptron
learning. Finally we present results, first for predictions based on threading
and then for energy minimization of crambin and of a set of 6 immunoglobulins.
The main result is that we proved that the two simple approximations we studied
for the free energy are not suitable for protein folding. Perspectives are
discussed in the last section.Comment: 29 pages, 10 figure
Increased sensitivity to cocaine-induced analgesia in Spontaneously Hypertensive Rats (SHR)
This study examined the analgesic effect of cocaine in Spontaneously Hypertensive Rats (SHR), which are considered a suitable model for the study of attention deficit hyperactivity disorder (ADHD), and in Wistar (WIS) rats of both sexes using the hot-plate test. In addition, we tested whether habituation to the unheated hot-plate apparatus, that "normalizes" the basal hypoalgesic phenotype of SHR, alters the subsequent cocaine-induced analgesia (CIA) in this strain. SHR of both sexes were hypoalgesic compared to WIS rats in the hot-plate test and showed higher sensitivity to CIA. Habituation to the unheated hot-plate reduced the basal nociceptive latency of SHR, suggesting cognitive/emotional modulation of pain in this strain, but did not alter the magnitude of CIA. The present study shows increased sensitivity to CIA in SHR, which may be related to abnormalities in the mesocorticolimbic dopaminergic system. Further studies using SHR strain may reveal new information on the neurobiological mechanisms underlying ADHD and its co-morbidity with drug addiction
The Origin of the Designability of Protein Structures
We examined what determines the designability of 2-letter codes (H and P)
lattice proteins from three points of view. First, whether the native structure
is searched within all possible structures or within maximally compact
structures. Second, whether the structure of the used lattice is bipartite or
not. Third, the effect of the length of the chain, namely, the number of
monomers on the chain. We found that the bipartiteness of the lattice structure
is not a main factor which determines the designability. Our results suggest
that highly designable structures will be found when the length of the chain is
sufficiently long to make the hydrophobic core consisting of enough number of
monomers.Comment: 17 pages, 2 figure
Characterization of pairs of toxic and nontoxic misfolded protein oligomers elucidates the structural determinants of oligomer toxicity in protein misfolding diseases
Conspectus: The aberrant misfolding and aggregation of peptides and proteins into amyloid aggregates occurs in over 50 largely incurable protein misfolding diseases. These pathologies include Alzheimer’s and Parkinson’s diseases, which are global medical emergencies owing to their prevalence in increasingly aging populations worldwide. Although the presence of mature amyloid aggregates is a hallmark of such neurodegenerative diseases, misfolded protein oligomers are increasingly recognized as of central importance in the pathogenesis of many of these maladies. These oligomers are small, diffusible species that can form as intermediates in the amyloid fibril formation process or be released by mature fibrils after they are formed. They have been closely associated with the induction of neuronal dysfunction and cell death. It has proven rather challenging to study these oligomeric species because of their short lifetimes, low concentrations, extensive structural heterogeneity, and challenges associated with producing stable, homogeneous, and reproducible populations. Despite these difficulties, investigators have developed protocols to produce kinetically, chemically, or structurally stabilized homogeneous populations of protein misfolded oligomers from several amyloidogenic peptides and proteins at experimentally ameneable concentrations. Furthermore, procedures have been established to produce morphologically similar but structurally distinct oligomers from the same protein sequence that are either toxic or nontoxic to cells. These tools offer unique opportunities to identify and investigate the structural determinants of oligomer toxicity by a close comparative inspection of their structures and the mechanisms of action through which they cause cell dysfunction. This Account reviews multidisciplinary results, including from our own groups, obtained by combining chemistry, physics, biochemistry, cell biology, and animal models for pairs of toxic and nontoxic oligomers. We describe oligomers comprised of the amyloid-β peptide, which underlie Alzheimer’s disease, and α-synuclein, which are associated with Parkinson’s disease and other related neurodegenerative pathologies, collectively known as synucleinopathies. Furthermore, we also discuss oligomers formed by the 91-residue N-terminal domain of [NiFe]-hydrogenase maturation factor from E. coli, which we use as a model non-disease-related protein, and by an amyloid stretch of Sup35 prion protein from yeast. These oligomeric pairs have become highly useful experimental tools for studying the molecular determinants of toxicity characteristic of protein misfolding diseases. Key properties have been identified that differentiate toxic from nontoxic oligomers in their ability to induce cellular dysfunction. These characteristics include solvent-exposed hydrophobic regions, interactions with membranes, insertion into lipid bilayers, and disruption of plasma membrane integrity. By using these properties, it has been possible to rationalize in model systems the responses to pairs of toxic and nontoxic oligomers. Collectively, these studies provide guidance for the development of efficacious therapeutic strategies to target rationally the cytotoxicity of misfolded protein oligomers in neurodegenerative conditions
The Hsp70 Chaperone System Stabilizes a Thermo-sensitive Subproteome in E. coli
Stress-inducible molecular chaperones have essential roles in maintaining protein homeostasis, but the extent to which they affect overall proteome stability remains unclear. Here, we analyze the effects of the DnaK (Hsp70) system on protein stability in Escherichia coli using pulse proteolysis combined with quantitative proteomics. We quantify similar to 1,500 soluble proteins and find similar to 500 of these to be protease sensitive under normal growth conditions, indicating a high prevalence of conformationally dynamic proteins, forming a metastable subproteome. Acute heat stress results in the unfolding of an additional similar to 200 proteins, reflected in the exposure of otherwise buried hydrophobic regions. Overexpression of the DnaK chaperone system markedly stabilizes numerous thermo-sensitive proteins, including multiple ribosomal proteins and large, hetero-oligomeric proteins containing the evolutionarily ancient c.37 fold (P loop nucleoside triphosphate hydrolases). Thus, the Hsp70 system, in addition to its known chaperone functions, has a remarkable capacity to stabilize proteins in their folded states under denaturing stress conditions
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