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The Tell-Tale Brain V. The Autistic Brain Richard Panek.

1. Introduction

Rest Alex Soojung-Kim Pang. Introducing Mind and Brain Angus Gellatly. Codependent - Now What? Hodges' Frontotemporal Dementia Bradford C. Why We Sleep Matthew Walker. Genius Foods Max Lugavere. Brain Stimulation in Psychiatry Charles H. Selfless Insight James H. The Wahls Protocol Terry Wahls.

The Polyvagal Theory Stephen W. Insomniac City Bill Hayes. Migraine Miracle Josh Turknett. Descartes' Error Antonio Damasio. Principles of Behavioral Genetics Robert R. Other books in this series. Mass Spectrometry and Genomic Analysis J. Guide to Biomolecular Simulations Oren M. Table of contents 1. Cross-Beta Models and Flexibility. Evidence from the Bioinformatics Analyses. Another Illustration of the D2 Concept.

Tan and Kah-Leong Lim. Hoozemans and Wiep Scheper. Ubiquitin Proteasome System and Autophagy. Another example of surfaces favouring protein folding is provided by the large family of the above mentioned NUPs [ 26 ]. These apparently structurally and functionally unrelated proteins include many transcription factors, ribosomal proteins and signalling proteins involved in the cell cycle control at the transcriptional and translational levels.

Unstructured domains are also found in certain regions of other proteins that are otherwise natively folded. A recent search in the Swiss Protein Database has led to the prediction that over 15, proteins could contain disordered regions of at least 40 consecutive residues and over proteins could be completely disordered [ 31 ]. This observation indicates that significant segments of the eukaryotic genomes encode long stretches of amino acid residues that, at least under some conditions, are likely to be unfolded or to adopt non-globular structures of unknown nature.

NUPs are usually easily recognizable from their amino acid content as they generally display a low mean hydrophobicity and a high net charge. These characteristics, thought to be the molecular basis by which these proteins remain unfolded in the absence of partners, are also able to reduce their intrinsic tendency to aggregate in the highly crowded intracellular milieu [ 32 ]. Here, the unstructured state of most NUPs favours their binding to the molecular chaperones during their short living time before they interact with their specific target proteins [ 26 ].

Actually, many NUPs adopt specific three-dimensional structures upon interaction with their specific target proteins that are thought to provide them a surface suitable to allow their folding [ 34 ]. It is also possible that the target protein provides some structural information needed for the specific NUP to reach its correct fold, in particular charged and hydrophobic residues complementing its structural deficiencies Alternatively, NUPs undergo rapid intracellular turnover by the cellular clearance mechanisms [ 33 ].

The latter feature could be an advantage for certain cellular functions, providing a further level of control to enable the cell to respond rapidly and effectively to perturbations in the cellular environment. Until it was commonly believed that the ability to polymerize into ordered fibrillar aggregates of amyloid type was a shared property of the few proteins and peptides found aggregated in tissue in the various amyloid diseases possibly arising from some structural peculiarity.

However, in it was found that two proteins unrelated to any amyloid pathology were able to aggregate in vitro into fibrillar assemblies undistinguishable from the classical amyloid fibrils [ 35 , 36 ]. Since then, it has increasingly been recognized that the tendency to aggregate into amyloid assemblies is a general property of the peptide backbone of proteins and peptides. Such a tendency arises from the primordial tendency of polypeptide chains to self-organize into polymeric assemblies stabilized by hydrogen bonds between parallel or anti-parallel polypeptide stretches in the beta-strand conformation provided by the monomers.

The resulting polymers display the ordered cross-beta structure that characterizes the amyloid fold reviewed in [ 4 ]. This does not imply that the side chains of the polypeptide chain are not important; rather, they determine the environmental conditions under which the polypeptide chain can undergo aggregation. This view considers natural proteins as a group of evolved amino acid polymers whose the amino acid sequences disfavour aggregation whilst favouring folding into compact states resulting mainly from the tertiary interactions among the side chains that shield the peptide backbone.

Conversely, protein aggregation into amyloid, which is mainly stabilized by secondary interactions, is considered the expression of the intrinsic primordial tendency of the peptide backbone to give secondary intermolecular interactions between backbone groups reviewed in [ 4 ]. Another consequence of such a paradigm is that protein folding and protein aggregation must be distinct but competing pathways the same polypeptide chain can undergo depending on the environmental conditions Figure 3.

Accordingly, extensive studies have been carried out in vitro to investigate the transition between natively folded states and soluble aggregate-precursor states and between the latter and mature amyloid fibrils [ 37 ]. A combined energy landscape model for protein folding left and aggregation right starting from the unfolded ensemble. Both sides display considerable roughness, but amyloid fibrils display a remarkably higher stability and lower energy content than the natively folded structure.

The picture highlights the multitude of the different conformational states available to a protein when they are stabilized by either intramolecular monomeric protein or intermolecular aggregation intermediates and mature fibrils contacts. The presence of intermolecular contacts increases dramatically the ruggedness of the landscape for protein aggregation with respect to what is shown in the folding side.

The picture highlights energy barriers that a monomeric polypeptide chain either unfolded or natively folded must overcome to gain access to the aggregation landscape generating aggregation nuclei, often the rate-limiting step of the aggregation process. The energy barriers can be lowered by the presence of suitable surfaces.

Modified from [ 40 ]. As it has been pointed out above, the intracellular macromolecular milieu is likely to favour compact states such as those arising from protein folding or protein aggregation. These findings confirm that protein folding and protein aggregation are pathways in close competition to each other and that any polypeptide chain can undergo either pathway depending on both its structural and physicochemical features and medium conditions.

The view that protein folding and aggregation are competing paths considers both as distinct yet not mutually excluding processes relying on a more general energy landscape including conformational states not involved in protein folding, yet potentially accessible to a polypeptide chain [ 39 ]. The two sides of the protein energy landscape highlight the competition between intramolecular folding and intermolecular aggregation interactions, which increases considerably the roughness of the whole landscape.

The scheme depicted in Figure 3 modified from [ 40 ] suggests, at least in part, the complexity of the overall protein folding and aggregation energy landscape. It includes some of the main conformational states a polypeptide chain can get during its self-organization paths eventually culminating with the appearance of thermodynamically favoured compact monomeric or polymeric states [ 39 ].

Either stable final compact state may be even more favoured thermodynamically in a living cell by the macromolecular crowding and its excluded volume effects see above. The generation of oligomeric aggregation nuclei is considered a key step at the onset of protein aggregation, accounting for the delay times of polymer appearance that are recorded by in in vitro protein aggregation experiments. However, at variance with protein folding, where in depth investigations carried out in the last decade have provided significant information on the structural features of folding intermediates and transition states, much less knowledge is currently available on the conformational states available to an aggregating polypeptide chain; the structural features, at the atomic level, of the oligomeric assemblies arising in the path of protein aggregation are substantially unknown as well.

Extensive investigation on alpha-synuclein has shown that, in this case, the transient oligomeric species are rich in beta-sheet, expose hydrophobic clusters and display a partially folded structure [ 40 , 41 ]. Actually, some of the energy minima in the aggregation side of the energy landscape are expected to be poorly defined due to the broad heterogeneity of unstable, rapidly interconverting oligomeric states endowed with comparable free energies.

On the contrary, the energy minima of the much more structurally defined stable higher order species protofibrils, protofilaments and mature fibrils can be much more easily identifiable, even though fibrils with different morphologies and structural differences can be formed under different solution conditions [ 42 ]. For example, the stabilities, and hence the energy minima, of mature amyloid fibrils, and their structural variants, are expected to be more pronounced than those of their natively folded monomers considering the reduced molecular dynamics and the consistency of the ordered core structure of the fibrils.

The nucleation-dependent polymerization mechanism of fibril growth, whose physical basis approaches that of the ordered assembly occurring in crystal growth, also supports fibril stability and represents a key difference between protein folding and aggregation. It is possible to shift a protein from the folding to the aggregation side of its energy landscape by modifying its structural features mutations, truncations, amino acid chemical modifications or the environmental conditions temperature, pH, medium composition.

In most cases, protein aggregation can be started in the presence of mildly destabilising medium conditions, such as mild shifts of the temperature or the pH or the presence of moderate amounts of denaturing agents or of co-solvents such as trifluoroethanol; the latter modifies the dielectric constant of the solution increasing the stability of the secondary contacts while reducing that of the tertiary ones [ 43 — 45 ].

Under these conditions, a folded protein populates partially unfolded states by opening its closely packed structure, thus exposing aggregation-prone regions normally buried into the hydrophobic core and the peptide backbone, that is shielded by the side chains in the compactly folded state.

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These partially unfolded structures can bear similarities to the folding intermediates [ 38 , 46 , 47 ] or to some of the near-native conformations in dynamic equilibrium with a folded protein. The link between native state dynamics and fibrillar aggregation of a protein has been highlighted in the case of lysozyme by mass spectrometry experiments [ 48 ]. In the lysozyme, the relative instability of the partially folded precursors is the driving force allowing them to re-organize into still poorly stable, and often thermodynamically disfavoured, transient aggregation nuclei rich in beta structure, established between stretches of polypeptide chains in the beta strand conformation [ 48 ].

Nucleation is the rate limiting step of the aggregation process and occurs during the lag phase; its kinetics can depend on the protein and medium conditions, whereas subsequent nuclei elongation is thermodynamically favourable and proceeds until completion of fibril assembly. Spherical oligomers and other pre-fibrillar forms, including curvy protofibrils, can be formed instead of aggregation nuclei and appear to result from a nucleation-independent path in the absence of any lag phase [ 49 — 52 ]. In this case, it is not clear whether these forms are on-pathway, growing by direct binding of monomers, or off-pathway, representing dead-end intermediates [ 51 , 53 — 55 ].

Studies on betamicroglobulin b2-m have provided information on this issue. It has been shown that, depending on protein structural features and medium conditions, b2-m exists in different aggregation states; for b2-m and other proteins, some of these states oligomeric species and beaded protofibrils are off-pathway products [ 42 , 51 , 56 ] arising from the polymerization of partially folded species retaining significant amount of native structure and involving some of the native beta strands [ 57 ]. The latter species are different from the oligomers appearing in the fibrillization path, which involve extensive structural rearrangement into the stable cross-beta structure of amyloid fibrils [ 52 ].

Almost no information is currently available on the energy barriers a folded or a partially unfolded protein must overcome to gain access to the conformational spaces allowing it to re-organize into aggregation nuclei; however, it is believed that these structural transitions can be favoured, among others, by surfaces Figure 3. This is a key issue, considering that the intracellular environment provides an extremely large surface area.

Actually, surfaces, either biological or synthetic, can enhance protein misfolding and speed aggregation see below besides favouring protein folding in special cases see above. Finally, recent findings have shown that, at least in some cases, a protein can aggregate by initially populating monomeric or oligomeric states where it maintains substantially its natively folded structure before subsequently undergoing conformational rearrangements into amyloids Figure 4.

In addition to the natively folded beaded protofibrils of b2-m see above , other proteins have been proposed to undergo ordered fibrillar polymerization retaining their native fold at least in the initial steps. These include tranthyretin, for which a model with direct stacking of natively folded monomeric subunits has been proposed [ 58 ], T7 endonuclease I [ 59 ], p13suc1 [ 60 ], and the serpins reviewed in [ 61 ] , where a domain swapping mechanism has been depicted.

A similar mechanism could also underlie the generation of native-like fibrils by the yeast prion Ure2p [ 62 ] and the first step of the amyloid aggregation of the Sso acylphosphatase [ 63 ]. The nucleation of oligomeric pre-fibrillar aggregates is the key, as well as the rate-limiting, step in the path eventually culminating with amyloid fibril formation. Recently, it has been reported that, in some cases, protein aggregation can start from natively folded states organising into oligomers.

The latter can further grow into native-like fibrils, as in the case of serpins or Ure2p or, alternatively undergo conformational rearrangement populating misfolded pre-fibrillar aggregates. As stated above, proteins are synthesized and fold in a very complex environment where they are in close contact with other molecules and with biological surfaces such as membranes and macromolecular assemblies favouring, in some cases, their correct folding.

However, biological surfaces, notably lipid membranes, can also affect the conformation of the interacting proteins populating secondary structure-based aberrant states of the polypeptide chain [ 64 , 65 ] thus modifying lipid arrangement with possible membrane disruption [ 66 , 67 ]. Actually, pre-fibrillar assemblies can grow on nanoparticles [ 68 ], anionic surfaces such as mica, fatty acid and SDS micelles, and anionic phospholipid vesicles [ 69 — 71 ], synthetic phospholipid bilayers [ 72 — 78 ] and cell membranes [ 79 , 80 ], modifying membrane structure and permeability and impairing the function of specific membrane-bound proteins and signalling pathways [ 81 , 82 ].

These studies carried out mainly with synthetic surfaces, have prompted increasing interest on the role of surfaces in protein aggregation and on the relation of the latter to the membrane structure and lipid composition. Distribution of the molecules in a three-dimensional A or in a two-dimensional B space such as those provided by the bulk solution or by a surface, respectively. In a 3D space, the average distance between protein molecules is in relation to the cube root of the total number of molecules whereas in a 2D space this depends on the square root of the number of molecules.

As a consequence, for concentrations above 1 nM the same number of protein molecules typically are much closer to each other in a two-dimensional space than in the corresponding three dimensional space. Therefore, surfaces can locally increase protein concentration favouring reciprocal interactions and speeding aggregate nucleation. The effects of a surface on protein misfolding and aggregation depend on the chemical features of the monomer, its folded or unfolded state, the way it interacts with the surface and the physicochemical properties of the latter, including its electrostatic potential and hydrophobicity reviewed in [ 83 ].

The physicochemical properties of the two-dimensional environment of a surface can be very different from those of the bulk aqueous phase. For monomer concentrations above 1 nM, surface adsorption reduces considerably the average distance among molecules respect to that in the three-dimensional bulk solution favouring monomer-monomer interactions, aggregate nucleation and insertion into the lipid bilayer [ 69 , 73 — 78 ] reviewed in [ 84 , 85 ] Figure 5 , eventually leading to membrane disorganization [ 65 , 67 ].

In addition, the strong electrostatic field or the non-polar environment of heavily charged or hydrophobic surfaces, respectively, can modify the protein fold with exposure to the surface of regions that normally are associated with each other through electrostatic or hydrophobic interactions [ 85 ]. This view agrees with experimental data showing that surfaces can catalyze the formation of amyloid aggregates by a mechanism substantially different from that occurring in the bulk solution [ 69 ].

In particular, hydrophobic or charged surfaces may induce local or more extensive unfolding resulting in the opening of the closely packed structure; concomitantly, hydrophobic groups normally buried into the compactly folded native state are allowed to interact with hydrophobic clusters exposed on the surface without paying the energy penalty resulting from the exposure of the same residues to the aqueous environment reviewed in [ 85 ].

As discussed above, these considerations apply to the behaviour of chaperones in assisting protein folding, to the target-induced folding of natively unfolded proteins as well as to the trafficking of protein molecules across membranes. However, not only membrane surfaces can be involved in protein aggregation.

For example, it has been proposed that b2-m aggregation can be favoured by monomer binding to the collagen triple helix, thus providing a possible explanation of the tissue-specificity of dialysis-related amyloidosis [ 88 ]; it has also been proposed that binding affinity fluctuations could influence the concentration of wild-type and N-truncated b2-m in the proximity of collagen fibers and hence their susceptibility to aggregation [ 89 ].

Finally, recent findings suggest that, in the presence of collagen, monomeric b2-m aggregates into amyloid fibrils sprouting from the surface of collagen fibres either in vivo and in vitro [ 90 ]. Glycosaminoglycans can also provide a surface suitable to promote growth of amyloid assemblies of gelsolin [ 91 ] and acylphosphatase [ 92 ]. In addition, other polyanions such as SDS and nucleic acids have been found to accelerate fibrillization of alpha-synuclein and the prion protein, respectively [ 70 , 93 ].

Finally, as stated above, clusters of anionic phospholipids have been shown to e enhance protein misfolding and aggregation [ 70 — 72 ] and preferentially recruit protein aggregates see below. Biological membranes may also be important in amyloid fibrillogenesis as the primary sources of the aggregating peptide monomers. Membrane environment is of fundamental importance in regulating membrane protein degradation by specific membrane proteases such as the secretases or the protein convertases.

This is best exemplified by the Abeta peptides resulting from APP processing [ 94 ], the ABri and ADan peptides resulting from BRI processing reviewed in [ 82 ] , the medin, and gelsolin peptides arising from lactadherin and gelsolin proteolysis, respectively [ 95 ] reviewed in [ 96 ] , as well as other peptides such as that arising from Pmel17 processing reviewed in [ 96 ].


Protein Folding and Misfolding on Surfaces

Conflicting data on the effect of membrane cholesterol on amyloid aggregate production and toxicity have been reported in the past years reviewed in [ 97 , 98 ]. On this aspect, the cholesterol-AD relation is paradigmatic reviewed in [ 99 ]. The positive relationship between hypercholesterolemia and risk of sporadic AD is known since long time, however a mechanistic explanation for such association has not yet been provided. Yet, many data suggest a protective effect of membrane cholesterol against aggregate cytotoxicity [ ]; in addition, a loss of cholesterol in brain leads to neurodegeneration and reduced levels of cholesterol are found in brains from AD patients [ ].

Possible clues on the effect of cholesterol on amyloid generation and interaction at the membrane level can be given by lipid rafts, ganglioside- and cholesterol-enriched dynamic membrane microdomains harbouring many membrane proteins including APP and secretases reviewed in [ ]. The increased presence of APP and secretases in lipid rafts may provide, at least in part, a theoretical framework for the observed increased AD risk in hypercholesterolemic people reviewed in [ 99 ].

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The generation of amyloidogenic peptides arising from membrane processing of other proteins reviewed in [ 83 , 96 ] could be affected by membrane lipid composition as well. The question as to whether amyloid fibrils are toxic to cells by themselves or, rather, they are harmless, stable reservoirs of toxic precursors stems from long time. Considering the difficulty to get structural information on the intermediates protofibrils preceding the appearance of mature fibrils see above , much interest has recently been focused on their morphological features, as shown by electron or atomic force microscopy.

The earliest protofibrils typically appear as globular assemblies 2. Such subpopulation of pre-fibrillar ring-shaped aggregates could account for amyloid toxicity, thus envisaging a basically common early biochemical mechanism of the latter through cell membrane permeabilization reviewed in [ 86 ] see also below in a way that resembles the mechanism of several microbial pore-forming toxins [ ]. Channels or pores formed by pre-fibrillar amyloid aggregates have been described in vitro for a number of peptides and proteins associated or not-associated with amyloid disease reviewed in [ 4 ] and characterized primarily by recording ion currents across biological or reconstituted membranes [ 77 ].

Besides recruiting protein monomers favouring their misfolding and aggregation, surfaces, notably cell membranes, can also bind actively the unstable oligomeric assemblies preceding the appearance of mature amyloid fibrils. The importance of the relation between membrane lipid composition and the ability of early aggregates of peptides and proteins to bind to and to disassemble membranes has been extensively investigated.

Many studies highlight the key role of either anionic surfaces and membranes containing anionic phospholipids; as specified above, the strong electrostatic field given by clusters of negative charges can favour protein unfolding and aggregate nucleation; however, clusters of negative charges can also be sites of preferential interaction with pre-fibrillar aggregates.

Protein Folding and Misfolding on Surfaces

Accordingly, it has been shown that pre-fibrillar assemblies interact with, and destabilise, synthetic phospholipid bilayers [ 73 — 76 , 78 , ] reviewed in [ 86 ] and cell membranes [ 79 , 80 ], modifying membrane permeability and impairing the function of specific membrane-bound proteins and signalling pathways [ 81 ]. The roles of cholesterol and gangliosides in modulating Abeta peptide generation and aggregation see above as well as membrane-aggregate interaction have also been extensively studied. Actually, it has recently been reported that pre-fibrillar aggregates supplemented to the cell culture media display reduced interaction with the cells and cytotoxicity upon enriching in cholesterol the cell membrane whereas the opposite effects were found in cholesterol-depleted cells [ , — ].

Although requiring more extensive research, these data support the idea that, in general, a higher membrane rigidity following increased cholesterol content can hinder aggregate interaction with the cell membranes thus enhancing membrane resistance against disassembly by the aggregates. Another question debated since long time is whether specific receptors for amyloids responsible of the amyloid-membrane interaction do exist on the cell membrane.

The surface of the cell membrane is crowded of protein molecules. It is therefore conceivable that amyloid oligomers contacting protein molecules sprouting from the cell membrane may interact more or less specifically with some of them. Since , the receptor for advanced glycation end products RAGE has been proposed as a major candidate as amyloid receptor [ ]. By competing for ligand binding with cell-surface RAGE, its plasma soluble form, sRAGE, might trap circulating ligands preventing their interaction with cell surface receptors.

Actually, sRAGE appears protective against cytotoxicity of transthyretin aggregates [ ] and its high plasma levels are associated with a reduced risk of several diseases including AD. Increasing plasma sRAGE is therefore considered a promising therapeutic target potentially preventing vascular damage and neurodegeneration [ ].

In addition to RAGE, several cell surface proteins, including voltage-gated [ ] or ligand-gated calcium channels such as the glutamate NMDA and AMPA receptors have also been considered as possible receptors or specific interaction sites for amyloids [ — ]. The presence of specific effects mediated through the preferential, or even specific, interaction with membrane proteins could, at least in part, explain the variable vulnerability to amyloids of different cell types [ ].

However, in spite of these and other data on specific interaction sites for amyloids, the tendency of early amyloid aggregates to interact with synthetic lipid membranes supports the idea that the interaction can be non-specific but, possibly, modulated by the membrane lipid content see above ; such an interaction can also be able, by itself, to impair cell viability by altering membrane structure and permeability.

The proposal is now supported by studies carried out both on synthetic phospholipid bilayers and on cell membranes showing that the function of specific membrane proteins is impaired by the interaction with misfolded species or their oligomers reviewed in [ 86 ] , [ ]. The presence of toxic aggregates inside or outside the cells impairs a number of functions ultimately leading to cell death by apoptosis or, less frequently, by necrosis [ 12 , , — ].

This is true even for aggregates formed from proteins not associated with amyloid disease, featuring cytotoxicity as a generic property of every amyloid aggregate possibly arising from their shared cross-beta structure reviewed in [ 4 ] [ ]. In general, intracellular oxidative stress in cells exposed to toxic aggregates has been related to some form of destabilisation of cell membranes resulting in the lack of appropriate regulation of membrane proteins such as specific enzymes, receptors and ion pumps [ 82 ].

The latter can result from structural modifications of the membrane following the interaction with the aggregates or their monomers see above , from membrane lipid peroxidation or from chemical modification of membrane ion pumps reviewed in [ 4 ] , [ , ]. The work carried on in the last ten years has provided significant steps forward in the knowledge of how a polypeptide chain folds into the unique compact and biologically active protein structure.

Increasing information exploiting new spectroscopic, imaging, computing and simulation techniques makes it likely that we are starting to unravel the protein folding code. This is expected to have important outcomes in many areas of genomics and structural biology, including a better knowledge of protein unfolding and aggregation. Actually, it has emerged that protein folding and protein ordered aggregation rely on the same physicochemical parameters thus stressing the key importance of the structural adaptations evolved in order to select amino acid sequences endowed with the lowest propensity to unfold and aggregate in the complex and crowded intracellular milieu.

It also led us to consider that protein folding and aggregation are processes closely related with a shared energy landscape where different conformational states most often in equilibrium to each other can be populated. Finally, the increased knowledge on the fundamentals of protein folding, misfolding and aggregation enables us to better understand the effects, on these, of external factors, such as temperature, pH, mutations, chemical modifications, molecular crowding and surfaces.

In particular, the latter are increasingly recognised as important elements affecting remarkably the behaviour of a polypeptide chain providing it an environment with special physicochemical features, most often very different from those encountered in the bulk solution. Increasing data on the roles of surfaces in protein folding, misfolding and aggregation highlight contrasting effects. Some surfaces, such as those resulting from protein evolution, are able to promote protein folding over aggregation, as in the case of the molecular chaperones and the specific targets of the natively unstructured proteins.

However, in other cases synthetic or biological surfaces can favour protein misfolding and aggregation over normal folding, as it is shown by a number of experimental results carried out on synthetic phospholipid membranes or SDS micelles, inorganic surfaces such as mica, or macromolecules such as glycosaminoglycans, collagen and nucleic acids. In some cases, these researches have shed light on the possible factors favouring the aggregation of specific proteins such as b2m and on the tissue specificity of the deposition of its aggregates. In conclusion, it can be expected that the knowledge gained from protein folding and aggregation studies will give new insights into the nature of amyloid diseases and will help to provide a more rational basis for novel therapeutic strategies.

National Center for Biotechnology Information , U. Int J Mol Sci. Published online Dec 9. This article has been cited by other articles in PMC. Abstract Protein folding, misfolding and aggregation, as well as the way misfolded and aggregated proteins affects cell viability are emerging as key themes in molecular and structural biology and in molecular medicine. Protein folding, protein misfolding, protein aggregation, amyloid, amyloid fibrils, amyloid cytotoxicity. Introduction Increasing interest of protein science researchers is currently focussed at unravelling the molecular basis of protein folding and of its counterpart, protein misfolding and aggregation, as well as of the mechanisms of aggregate toxicity to living systems.

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Prions and Protein Misfolding

Outline of amyloid fibril structure. Essentials of protein folding The protein folding problem has been a challenging issue shrouded in mystery for decades, until the development of the energy landscape theory. Protein folding on surfaces Most of the present knowledge on protein folding arises from a multi-disciplinary approach including the use of a variety of simulation and experimental measurements carried out on wild-type and side-directed mutants of the investigated proteins.

Protein folding and aggregation are competing pathways Until it was commonly believed that the ability to polymerize into ordered fibrillar aggregates of amyloid type was a shared property of the few proteins and peptides found aggregated in tissue in the various amyloid diseases possibly arising from some structural peculiarity.

Aggregate nucleation from unfolded or natively folded states. Distribution of molecules in a 3D or a 2D space. Biological surfaces are primary sites of amyloid interaction and toxicity The question as to whether amyloid fibrils are toxic to cells by themselves or, rather, they are harmless, stable reservoirs of toxic precursors stems from long time. Conclusions The work carried on in the last ten years has provided significant steps forward in the knowledge of how a polypeptide chain folds into the unique compact and biologically active protein structure. Alternative conformation of amyloidogenic proteins and their multi-step assembly pathways.

The structural basis of protein folding and its links with human disease. Stefani M, Dobson CM. Protein aggregation and aggregate toxicity: New insights into protein folding, misfolding diseases and biological evolution. Probing the mechanism of amyloidogenesis through a tandem repeat of the PI3-SH3 domain suggests a generic model for protein aggregation and fibril formation. The protofilament substructure of amyloid fibrils. Common core structure of amyloid fibrils by synchrotron X-ray diffraction. Progress towards a molecular-level structural understanding of amyloid fibrils.

Functional amyloid formation within mammalian tissue. Monitoring the process of HypF fibrillization and liposome permeabilization by protofibrils. Huntingtin spheroids and protofibrils as precursors in polyglutamine fibrillization. Tetramer dissociation and monomer partial unfolding precedes protofibril formation in amyloidogenic transthyretin variants. Correlation of synaptic and pathological markers with cognition of the elderly. Sitia R, Braakman I.

Quality control in the endoplasmic reticulum protein factory. AAA proteases of mitochondria: Quality control of membrane proteins and regulatory function during mitochondrial biogenesis. Protein degradation and protection against misfolded or damaged proteins. Rapid degradation of a large fraction of newly synthesized proteins by proteasomes.