Gerstmann-Sträussler-Scheinker Disease Amyloid Protein Polymerizes According to the “Dock-and-Lock” Model

Gobbi, Marco; Colombo, Laura; Morbin, Michela; Mazzoleni, Giulia; Accardo, Elena; Vanoni, Marco; Favero, Elena Del; Cantù, Laura; Kirschner, Daniel A.; Manzoni, Claudia; Beeg, Marten; Ceci, Paolo; Ubezio, Paolo; Forloni, Gianluigi; Tagliavini, Fabrizio; Salmona, Mario

doi:10.1074/jbc.m506164200

Cited by 34 publications

(28 citation statements)

References 35 publications

(44 reference statements)

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“…These results can be interpreted by assuming that before pressure treatment two populations of PrP fibrils coexist in the sample; that is, a "partially locked" (reversibly bound monomers) form that can be dissociated and a "totally locked" form (irreversibly bound monomers) that cannot be dissociated. These two conformers are currently thought to be different states occurring during amyloidogenesis (73)(74)(75)(76). Yet the structural differences between these two initial and co-existing populations of fibrils appear to be subtle.…”

Section: Discussionmentioning

confidence: 99%

Amyloid Features and Neuronal Toxicity of Mature Prion Fibrils Are Highly Sensitive to High Pressure

Moustaine

Perrier

et al. 2011

Journal of Biological Chemistry

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Prion proteins (PrP) can aggregate into toxic and possibly infectious amyloid fibrils. This particular macrostructure confers on them an extreme and still unexplained stability. To provide mechanistic insights into this self-assembly process, we used high pressure as a thermodynamic tool for perturbing the structure of mature amyloid fibrils that were prepared from recombinant full-length mouse PrP. Application of high pressure led to irreversible loss of several specific amyloid features, such as thioflavin T and 8-anilino-1-naphthalene sulfonate binding, alteration of the characteristic proteinase K digestion pattern, and a significant decrease in the ␤-sheet structure and cytotoxicity of amyloid fibrils. Partial disaggregation of the mature fibrils into monomeric soluble PrP was observed. The remaining amyloid fibrils underwent a change in secondary structure that led to morphologically different fibrils composed of a reduced number of proto-filaments. The kinetics of these reactions was studied by recording the pressure-induced dissociation of thioflavin T from the amyloid fibrils. Analysis of the pressure and temperature dependence of the relaxation rates revealed partly unstructured and hydrated kinetic transition states and highlighted the importance of collapsing and hydrating inter-and intramolecular cavities to overcome the high free energy barrier that stabilizes amyloid fibrils.Amyloid fibrils are filamentous polypeptide aggregates that are associated with devastating disorders such as Alzheimer and Parkinson diseases, type II diabetes, and prion (proteinaceous infectious particle) diseases, including Creutzfeldt-Jakob and mad cow disease (1, 2). There is increasing evidence that under appropriate conditions the amyloid state is accessible also to many other proteins that are not related to diseases, suggesting that the amyloid state is a generic structural feature, which might be adopted by any polypeptide chain (3-6).The development of in vitro model systems together with various biophysical and biochemical techniques (7-9) has improved the knowledge on the physicochemical basis of amyloid formation as well as on their structural and biochemical properties. It is now well recognized that a common property of amyloid fibrils is the extensive stacking of intermolecular ␤-strands that are arranged perpendicularly to the fibril axis and stabilized by a dense network of non-covalent interactions (10 -13). These fibrils consist of a variable number and arrangement of thin assemblies called proto-filaments that give rise to different fibril morphologies of diameters between 5 and 30 nanometers, both in in vitro preparations or in tissues (14 -22). Fibrils and their precursors are generally cytotoxic (23, 24) and are, thus, thought to be responsible for the neurodegeneration that is associated with many amyloid diseases.Yet the fundamental parameters that govern the protein aggregation process and dictate fibril stability/clearance are not well known. As the study of protein folding has been greatly advanc...

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Section: Discussionmentioning

confidence: 99%

Amyloid Features and Neuronal Toxicity of Mature Prion Fibrils Are Highly Sensitive to High Pressure

Moustaine

Perrier

et al. 2011

Journal of Biological Chemistry

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“…The kinetics of aggregation of PrP 82-146 was investigated by Gobbi et al (2006), who proposed a "dock-and-lock" model to explain the mechanism of polymerization. Structural analysis found profound differences between the wild-type and partially scrambled PrP 82-146 peptides in their propensity to aggregate , amyloid formation being significantly reduced or prevented when either region 106 -126 or 127-146 was disrupted.…”

Section: Discussionmentioning

confidence: 99%

Neurotoxic and Gliotrophic Activity of a Synthetic Peptide Homologous to Gerstmann–Sträussler–Scheinker Disease Amyloid Protein

et al. 2007

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“…Taking advantage of these advances, we have performed all-atom MD simulations to describe the molecular events in the growth process of amyloid fibrils. Several experiments have suggested that the kinetics of monomer incorporation is complex but can be described by a dock-lock mechanism (19,(33)(34)(35). In this scenario, which can be rationalized by using an energy landscape perspective (36, 37), the addition of the monomer is envisioned to occur in 2 distinct global stages.…”

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confidence: 99%

Dynamics of locking of peptides onto growing amyloid fibrils

Reddy¹,

Straub

Thirumalai

2009

Proc. Natl. Acad. Sci. U.S.A.

120

147

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Sequence-dependent variations in the growth mechanism and stability of amyloid fibrils, which are implicated in a number of neurodegenerative diseases, are poorly understood. We have carried out extensive all-atom molecular dynamics simulations to monitor the structural changes that occur upon addition of random coil (RC) monomer fragments from the yeast prion Sup35 and A␤-peptide onto a preformed fibril. Using the atomic resolution structures of the microcrystals as the starting points, we show that the RC 3 ␤-strand transition for the Sup35 fragment occurs abruptly over a very narrow time interval, whereas the acquisition of strand content is less dramatic for the hydrophobic-rich A␤-peptide. Expulsion of water, resulting in the formation of a dry interface between 2 adjacent sheets of the Sup35 fibril, occurs in 2 stages. Ejection of a small number of discrete water molecules in the second stage follows a rapid decrease in the number of water molecules in the first stage. Stability of the Sup35 fibril is increased by a network of hydrogen bonds involving both backbone and side chains, whereas the marginal stability of the A␤-fibrils is largely due to the formation of weak dispersion interaction between the hydrophobic side chains. The importance of the network of hydrogen bonds is further illustrated by mutational studies, which show that substitution of the Asn and Gln residues to Ala compromises the Sup35 fibril stability. Despite the similarity in the architecture of the amyloid fibrils, the growth mechanism and stability of the fibrils depend dramatically on the sequence.all-atom simulations ͉ amyloid growth dynamics ͉ growth mechanism of fibrils ͉ sequence-dependent addition process ͉ Sup35 and A␤-peptide A number of neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases and transmissible prion disorders are associated with the formation of amyloid protein fibrils with a characteristic ␤-structure. In addition to proteins directly implicated in diseases, others that are unrelated by sequence or structure also form fibrils rich in ␤-sheet structure (1). These observations make it urgent to understand the molecular basis of amyloid fibril formation (1-3). The structures of the amyloid fibrils share a characteristic cross-␤ motif (4-7) with the peptides (or the proteins) forming extended ␤-strands that span the length of the fibril. Depending on the sequence, the strands in a given sheet are arranged in a parallel or antiparallel manner (8, 9) and lie perpendicular to the fibril axis. The near-universal morphology of the fibrils (without consideration of strains) suggests that the global mechanism that drives their formation from monomers may be similar (3). Indeed, several variations of the nucleated polymerization mechanism (NPM) have been used to account for amyloid fibril formation (10-12). According to the NPM, fluctuations (induced by denaturation stress, for example) lead to monomer conformations that can associate with other monomers to form fluid-like oligomers. If the size of the...

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Gerstmann-Sträussler-Scheinker Disease Amyloid Protein Polymerizes According to the “Dock-and-Lock” Model

Cited by 34 publications

References 35 publications

Amyloid Features and Neuronal Toxicity of Mature Prion Fibrils Are Highly Sensitive to High Pressure

Amyloid Features and Neuronal Toxicity of Mature Prion Fibrils Are Highly Sensitive to High Pressure

Neurotoxic and Gliotrophic Activity of a Synthetic Peptide Homologous to Gerstmann–Sträussler–Scheinker Disease Amyloid Protein

Dynamics of locking of peptides onto growing amyloid fibrils

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