2,949 research outputs found
What makes a protein sequence a prion ?
Typical amyloid diseases such as Alzheimer's and Parkinson's were thought to exclusively result from de novo aggregation, but recently it was shown that amyloids formed in one cell can cross-seed aggregation in other cells, following a prion-like mechanism. Despite the large experimental effort devoted to understanding the phenomenon of prion transmissibility, it is still poorly understood how this property is encoded in the primary sequence. In many cases, prion structural conversion is driven by the presence of relatively large glutamine/asparagine (Q/N) enriched segments. Several studies suggest that it is the amino acid composition of these regions rather than their specific sequence that accounts for their priogenicity. However, our analysis indicates that it is instead the presence and potency of specific short amyloid-prone sequences that occur within intrinsically disordered Q/N-rich regions that determine their prion behaviour, modulated by the structural and compositional context. This provides a basis for the accurate identification and evaluation of prion candidate sequences in proteomes in the context of a unified framework for amyloid formation and prion propagation. Protein conformational disorders include several neurodegenerative diseases. These pathologies are initiated by conformational changes in specific polypeptides that, in many cases, result in their spontaneous self-assembly to form toxic amyloids. Prions are a subclass of amyloids with the ability to propagate in vivo, thus becoming infectious. Previous work with yeast prions has provided tremendous insight into prion propagation mechanism. These proteins contain glutamine/asparagine (Q/N) enriched prion forming domains (PFDs), which are both necessary and sufficient for propagation. We found that these domains include specific short amyloid-prone sequences, which are likely able to trigger the amyloid conversion of the complete prion protein. The amyloid potency of these short segments suffices to discriminate with high accuracy between Q/N rich domains with and without prion activity. Our data suggest a model for prions where a classical amyloid core is embedded in a sequence context that reduces the amyloid nucleation potential, resulting in sequences that are strongly dependent on seeding. This model should allow the identification of prion-like proteins in the human proteome and prediction of the deleterious effects of genetic mutations occurring in these particular proteins
What Makes a Protein Sequence a Prion?
Typical amyloid diseases such as Alzheimer's and Parkinson's were thought to exclusively result from de novo aggregation, but recently it was shown that amyloids formed in one cell can cross-seed aggregation in other cells, following a prion-like mechanism. Despite the large experimental effort devoted to understanding the phenomenon of prion transmissibility, it is still poorly understood how this property is encoded in the primary sequence. In many cases, prion structural conversion is driven by the presence of relatively large glutamine/asparagine (Q/N) enriched segments. Several studies suggest that it is the amino acid composition of these regions rather than their specific sequence that accounts for their priogenicity. However, our analysis indicates that it is instead the presence and potency of specific short amyloid-prone sequences that occur within intrinsically disordered Q/N-rich regions that determine their prion behaviour, modulated by the structural and compositional context. This provides a basis for the accurate identification and evaluation of prion candidate sequences in proteomes in the context of a unified framework for amyloid formation and prion propagation
Simple models of protein folding and of non--conventional drug design
While all the information required for the folding of a protein is contained
in its amino acid sequence, one has not yet learned how to extract this
information to predict the three--dimensional, biologically active, native
conformation of a protein whose sequence is known. Using insight obtained from
simple model simulations of the folding of proteins, in particular of the fact
that this phenomenon is essentially controlled by conserved (native) contacts
among (few) strongly interacting ("hot"), as a rule hydrophobic, amino acids,
which also stabilize local elementary structures (LES, hidden, incipient
secondary structures like --helices and --sheets) formed early
in the folding process and leading to the postcritical folding nucleus (i.e.,
the minimum set of native contacts which bring the system pass beyond the
highest free--energy barrier found in the whole folding process) it is possible
to work out a succesful strategy for reading the native structure of designed
proteins from the knowledge of only their amino acid sequence and of the
contact energies among the amino acids. Because LES have undergone millions of
years of evolution to selectively dock to their complementary structures, small
peptides made out of the same amino acids as the LES are expected to
selectively attach to the newly expressed (unfolded) protein and inhibit its
folding, or to the native (fluctuating) native conformation and denaturate it.
These peptides, or their mimetic molecules, can thus be used as effective
non--conventional drugs to those already existing (and directed at neutralizing
the active site of enzymes), displaying the advantage of not suffering from the
uprise of resistance
Law of Genome Evolution Direction : Coding Information Quantity Grows
The problem of the directionality of genome evolution is studied. Based on
the analysis of C-value paradox and the evolution of genome size we propose
that the function-coding information quantity of a genome always grows in the
course of evolution through sequence duplication, expansion of code, and gene
transfer from outside. The function-coding information quantity of a genome
consists of two parts, p-coding information quantity which encodes functional
protein and n-coding information quantity which encodes other functional
elements except amino acid sequence. The evidences on the evolutionary law
about the function-coding information quantity are listed. The needs of
function is the motive force for the expansion of coding information quantity
and the information quantity expansion is the way to make functional innovation
and extension for a species. So, the increase of coding information quantity of
a genome is a measure of the acquired new function and it determines the
directionality of genome evolution.Comment: 16 page
Without magic bullets: the biological basis for public health interventions against protein folding disorders
Protein folding disorders of aging like Alzheimer's and Parkinson's diseases currently present intractable medical challenges. 'Small molecule' interventions - drug treatments - often have, at best, palliative impact, failing to alter disease course. The design of individual or population level interventions will likely require a deeper understanding of protein folding and its regulation than currently provided by contemporary 'physics' or culture-bound medical magic bullet models. Here, a topological rate distortion analysis is applied to the problem of protein folding and regulation that is similar in spirit to Tlusty's (2010a) elegant exploration of the genetic code. The formalism produces large-scale, quasi-equilibrium 'resilience' states representing normal and pathological protein folding regulation under a cellular-level cognitive paradigm similar to that proposed by Atlan and Cohen (1998) for the immune system. Generalization to long times produces diffusion models of protein folding disorders in which epigenetic or life history factors determine the rate of onset of regulatory failure, in essence, a premature aging driven by familiar synergisms between disjunctions of resource allocation and need in the context of socially or physiologically toxic exposures and chronic powerlessness at individual and group scales. Application of an HPA axis model is made to recent observed differences in Alzheimer's onset rates in White and African American subpopulations as a function of an index of distress-proneness
The Problem of the "Prebiotic and Never Born Proteins"
It has been argued that the limited set of proteins used by life as we know
it could not have arisen by the process of Darwinian selection from all
possible proteins. This probabilistic argument has a number of implicit
assumptions that may not be warranted. A variety of considerations are
presented to show that the number of amino-acid sequences that need have been
sampled during the evolution of proteins is far smaller than assumed by the
argument.Comment: 14 Pages; International Journal of Astrobiology / FirstView Article /
October 2012, pp 1
Unified perspective on proteins: A physics approach
We study a physical system which, while devoid of the complexity one usually
associates with proteins, nevertheless displays a remarkable array of
protein-like properties. The constructive hypothesis that this striking
resemblance is not accidental leads not only to a unified framework for
understanding protein folding, amyloid formation and protein interactions but
also has implications for natural selection.Comment: 26 pages, 15 figures, to appear on Phys. Rev.
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