Catalytic amyloids for nucleotide hydrolysis.

The design of small peptides that assemble into catalytically active intermolecular structures has proven to be a successful strategy towards developing minimalistic catalysts that exhibit some of the unique functional features of enzymes. Among these, catalytic amyloids have emerged as a fruitful source to unravel many different activities. These assemblies can potentially have broad applications that range from biotechnology to prebiotic chemistry.

Metal Ions Can Modulate the Self-Assembly and Activity of Catalytic Peptide Amyloids.

Rational design of peptides has become a powerful tool to produce self-assembled nanostructures with the ability to catalyze different chemical reactions, paving the way to develop minimalistic enzyme-like nanomaterials. Catalytic amyloid-like assemblies have emerged among the most versatile and active, but they often require additional factors for activity. Elucidating how these factors influence the structure and activity is key for the design.

IGF2 prevents dopaminergic neuronal loss and decreases intracellular alpha-synuclein accumulation in Parkinson's disease models.

Parkinson's disease (PD) is the second most common late-onset neurodegenerative disease and the predominant cause of movement problems. PD is characterized by motor control impairment by extensive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). This selective dopaminergic neuronal loss is in part triggered by intracellular protein inclusions called Lewy bodies, which are composed mainly of misfolded alpha-synuclein (α-syn) protein.

Catalytically Active Amyloids as Future Bionanomaterials.

Peptides and proteins can aggregate into highly ordered and structured conformations called amyloids. These supramolecular structures generally have convergent features, such as the formation of intermolecular beta sheets, that lead to fibrillary architectures. The resulting fibrils have unique mechanical properties that can be exploited to develop novel nanomaterials.

Design and Testing of Synthetic Catalytic Amyloids Based on the Active Site of Enzymes.

The amyloid fold is nowadays recognized as an alternative conformation accessible to different proteins and peptides. The highly stable and ordered structural organization of amyloid fibrils can be exploited for the design of novel nanomaterials with emergent properties. Recent works have demonstrated that the functional features of the active site of enzymes can be partially recreated using this fold as a scaffold to develop catalytically active amyloids.

Recent High-Resolution Structures of Amyloids Involved in Neurodegenerative Diseases.

Amyloids are highly ordered aggregates composed of proteins or peptides. They are involved in several pathologies, including hallmark neurodegenerative disorders such as Alzheimer's (AD) and Parkinson's (PD). Individuals affected by these diseases accumulate in their brains amyloids inclusions composed of misfolded forms of a peptide (Aβ) and a protein (Tau) in AD and α-synuclein protein (α-Sn) in PD.

Catalytic Amyloids as Novel Synthetic Hydrolases.

Amyloids are supramolecular assemblies composed of polypeptides stabilized by an intermolecular beta-sheet core. These misfolded conformations have been traditionally associated with pathological conditions such as Alzheimer's and Parkinson´s diseases. However, this classical paradigm has changed in the last decade since the discovery that the amyloid state represents a universal alternative fold accessible to virtually any polypeptide chain.

Functional characterization of the ATPase-like activity displayed by a catalytic amyloid.

Background: Amyloids are highly ordered polypeptide aggregates stabilized by a beta-sheet structural core. Though classically associated to pathology, reports on novel functional roles of these proteins have increasingly emerged in the past decade. Moreover, the recent discovery that amyloids formed with rationally designed small peptides can exhibit catalytic reactivity has opened up new opportunities in both biology and biotechnology.

Prion-like characteristics of the bacterial protein Microcin E492.

Microcin E492 (Mcc) is a pore-forming bacteriotoxin. Mcc activity is inhibited at the stationary phase by formation of amyloid-like aggregates in the culture. Here we report that, in a similar manner as prions, Mcc naturally exists as two conformers: a β-sheet-rich, protease-resistant, aggregated, inactive form (Mcc), and a soluble, protease-sensitive, active form (Mcc).

Overcoming electrostatic repulsions during amyloid assembly: Effect of pH and interaction with divalent metals using model peptides.

Amyloids are polypeptide aggregates involved in many pathologies including Alzheimer's disease. Amyloid assembly is a complex process affected by different interactions including hydrogen bonding, van der Waals forces and electrostatic interactions. The highly regular amyloid structure allows for an arrangement of residues that forces side chains to be closely positioned, giving rise to potentially unfavorable interactions such as electrostatic repulsions.

Development of a novel catalytic amyloid displaying a metal-dependent ATPase-like activity.

Amyloids are protein aggregates of highly regular structure that are involved in diverse pathologies such as Alzheimer's and Parkinson's disease. Recent evidence has shown that under certain conditions, small peptides can self-assemble into amyloids that exhibit catalytic reactivity towards certain compounds. Here we report a novel peptide with a sequence derived from the active site of RNA polymerase that displays hydrolytic activity towards ATP.

Strain-dependent profile of misfolded prion protein aggregates.

Prions are composed of the misfolded prion protein (PrP(Sc)) organized in a variety of aggregates. An important question in the prion field has been to determine the identity of functional PrP(Sc) aggregates. In this study, we used equilibrium sedimentation in sucrose density gradients to separate PrP(Sc) aggregates from three hamster prion strains (Hyper, Drowsy, SSLOW) subjected to minimal manipulations.

The extent of protease resistance of misfolded prion protein is highly dependent on the salt concentration.

Transmissible spongiform encephalopathies are neurodegenerative diseases caused by prions in mammals. An aberrantly folded protein (PrP(Sc)) is the main component of these proteinaceous infectious particles. Prions exhibit strong resistance to protease digestion, which is typically exploited for biochemical discrimination from its native cellular form (PrP(C)).

Protein misfolding cyclic amplification of infectious prions.

Prions are proteinaceous infectious agents responsible for the transmission of prion diseases. The lack of a procedure for cultivating prions in the laboratory has been a major limitation to the study of the unorthodox nature of this infectious agent and the molecular mechanism by which the normal prion protein (PrP(C)) is converted into the abnormal isoform (PrP(Sc)). Protein misfolding cyclic amplification (PMCA), described in detail in this protocol, is a simple, fast and efficient methodology to mimic prion replication in the test tube.

High-resolution structure of infectious prion protein: the final frontier.

Prions are the proteinaceous infectious agents responsible for the transmission of prion diseases. The main or sole component of prions is the misfolded prion protein (PrP(Sc)), which is able to template the conversion of the host's natively folded form of the protein (PrP(C)). The detailed mechanism of prion replication and the high-resolution structure of PrP(Sc) are unknown.

Kosmotropic anions promote conversion of recombinant prion protein into a PrPSc-like misfolded form.

Prions are self-propagating proteins involved in transmissible spongiform encephalopaties in mammals. An aberrant conformation with amyloid-like features of a cell surface protein, termed prion protein (PrP), is thought to be the essential component of the infectious particle, though accessory co-factor molecules such as lipids and nucleotides may be involved. The cellular co-factors and environmental conditions implicated in PrP misfolding are not completely understood.

Generation of prions in vitro and the protein-only hypothesis.

Prions are self-propagating proteinaceous infectious agents capable of transmitting disease in the absence of nucleic acids. The nature of the infectious agent in prion diseases has been at the center of passionate debate for the past 30 years. However, recent reports on the in vitro generation of prions have settled all doubts that the misfolded prion protein (PrP(Sc)) is the key component in propagating infectivity.

Molecular cross talk between misfolded proteins in animal models of Alzheimer's and prion diseases.

The central event in protein misfolding disorders (PMDs) is the accumulation of a misfolded form of a naturally expressed protein. Despite the diversity of clinical symptoms associated with different PMDs, many similarities in their mechanism suggest that distinct pathologies may cross talk at the molecular level. The main goal of this study was to analyze the interaction of the protein misfolding processes implicated in Alzheimer's and prion diseases.

Domain folding and flexibility of Escherichia coli FtsZ determined by tryptophan site-directed mutagenesis.

FtsZ has two domains, the amino GTPase domain with a Rossmann fold, and the carboxyl domain that resembles the chorismate mutase fold. Bioinformatics analyses suggest that the interdomain interaction is stronger than the interaction of the protofilament longitudinal interfaces. Crystal B factor analysis of FtsZ and detected conformational changes suggest a connection between these domains.