Protein Misfolding and Amyloid Formation for the Peptide GNNQQNY from Yeast Prion Protein Sup35: Simulation by Reaction Path Annealing

Lipfert, Jan; Franklin, Joel; Wu, Fang; Doniach, Sebastian

doi:10.1016/j.jmb.2005.03.083

Cited by 65 publications

(69 citation statements)

References 43 publications

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“…The structure of the aggregates from simulations satisfies the constraints derived from the experimental data, although the detailed atomic structure differs from the model proposed by Kammerer et al (7). Most strikingly, we observe in the course of simulations that several peptides form a ␤-sheet that acts as a template to convert an ␣-helix into a ␤-strand, in the absence of any artificial constraints (8,12,13). This provides direct support of the hypothesis by Prusiner (3) of the template-based aggregation scheme for prion proteins.…”

supporting

confidence: 63%

“…To facilitate the conversion, the authors covalently connected the two peptides by a short polyglycine segment. Lipfert et al (12) employed a reaction path annealing algorithm to study the misfolding and amyloid formation of a short seven-residue peptide from the yeast prion protein in the presence of pre-made ␤-sheets. In this algorithm, the initial and final states are fixed, and the energy is computed along the pathway by multiple constrained simulations.…”

mentioning

confidence: 99%

“…These studies provide computational evidence for the template model of propagating conformational changes proposed by Prusiner (3) that explains the lethal infection of pathological prions. However, to enable the sampling of the vast available conformational spaces, these computational studies either constrain the peptide systems between the folded and misfolded peptides (8,12) or "freeze" the misfolded template into a pre-assumed ␤-sheet aggregate (8,12,13) within the close proximity of the folded peptide. Thus, it is possible that these observed conformational inter-conversions are a result of the artificial biases present in the simulations.…”

mentioning

confidence: 99%

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Direct Observation of Protein Folding, Aggregation, and a Prion-like Conformational Conversion

Ding

LaRocque

Dokholyan

2005

Journal of Biological Chemistry

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Protein conformational transition from ␣-helices to ␤-sheets precedes aggregation of proteins implicated in many diseases, including Alzheimer and prion diseases. Direct characterization of such transitions is often hindered by the complicated nature of the interaction network among amino acids. A recently engineered small protein-like peptide with a simple amino acid composition features a temperature-driven ␣-helix to ␤-sheet conformational change. Here we studied the conformational transition of this peptide by molecular dynamics simulations. We observed a critical temperature, below which the peptide folds into an ␣-helical coiledcoil state and above which the peptide misfolds into ␤-rich structures with a high propensity to aggregate. The structures adopted by this peptide during low temperature simulations have a backbone root mean square deviation less than 2 Å from the crystal structure. At high temperatures, this peptide adopts an amyloid-like structure, which is mainly composed of coiled anti-parallel ␤-sheets with the cross-␤-signature of amyloid fibrils. Most strikingly, we observed conformational conversions in which an ␣-helix is converted into a ␤-strand by proximate stable ␤-sheets with exposed hydrophobic surfaces and unsaturated hydrogen bonds. Our study suggested a possible generic molecular mechanism of the templatemediated aggregation process, originally proposed by Prusiner (Prusiner, S. B. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 13363-13383) to account for prion infectivity.Protein conformation diseases, including Alzheimer, Lou Gehrig, and prion diseases (1), involve the aggregation of soluble proteins into insoluble amyloid fibrils following major conformational rearrangements. It has been shown that the amyloid fibrils formed by various proteins share a common core structure mainly composed of ␤-sheets (2). Thus, an intriguing conformational transition from ␣-helices to ␤-sheets occurs en route to the aggregation of natively ␣-helical proteins, such as prion proteins (3) in Creutzfeldt-Jakob disease and the A␤ peptide in Alzheimer disease (4). Understanding the molecular mechanism of such a transition is vital for the development of the final cure of amyloidogenic diseases (1).Despite the importance of this type of conformational transition, the detailed molecular mechanism is largely unknown. It has been shown that misfolded prion proteins are infectious even across species barriers (3). A template model proposed by Prusiner (3) explains prion infectivity. In this model, misfolded prions induce the conversion of nearby native prions to the misfolded state. However, the exact aggregation pathway and the driving forces have yet to be uncovered.Studies of molecular mechanisms and pathways are often hindered by complex interaction networks among the amino acids and in some cases by the large sizes of proteins related to these diseases. It has been shown that aggregation into amyloid fibrils is a common property of polypeptides (5, 6). Therefore, simple proteins and peptide systems can s...

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supporting

confidence: 63%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Direct Observation of Protein Folding, Aggregation, and a Prion-like Conformational Conversion

Ding

LaRocque

Dokholyan

2005

Journal of Biological Chemistry

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“…The isolated Sup35 prion segment peptide is predominantly in a random coil (23,38) [ Fig. 1 and supporting information (SI) Fig.…”

Section: Resultsmentioning

confidence: 99%

Dynamics of locking of peptides onto growing amyloid fibrils

Reddy¹,

Straub

Thirumalai

2009

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

122

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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“…71,86 Alternatively, the critical issue could be the interdigitation of side chains in the b-rich structure stabilizing it via hydrophobic interactions and allowing Van der Waals attractions favorable for amyloid formation to be maximized, while avoiding electrostatic repulsions. 71,87 When a short peptide derived from the Sup35 prion domain was used to model the structure of the cross-b-spine, Lipfert et al 88 found support for the polar zipper formation, whereas Nelson et al 63 predicted that Q and N side-chains were interdigitated to form a dry, tightly self-complementing steric zipper between two b-sheets. Whether prion amyloids are composed of polar or steric zippers, the positions of specific Q or N residues may be critical for efficient cross-seeding.…”

Section: How Might Heterologous Prionogenic Proteins Interact and Whamentioning

confidence: 99%

Prion-Prion Interactions

Derkatch

Liebman²

2007

Prion

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Published previously online as a Prion AbStrActThe term prion has been used to describe self-replicating protein conformations that can convert other protein molecules of the same primary structure into its prion conformation. Several different proteins have now been found to exist as prions in Saccharomyces cerevisiae. Surprisingly, these heterologous prion proteins have a strong influence on each others' appearance and propagation, which may result from structural similarity between the prions. Both positive and negative effects of a prion on the de novo appearance of a heterologous prion have been observed in genetic studies. Other examples of reported interactions include mutual or unilateral inhibition and destabilization when two prions are present together in a single cell. In vitro work showing that one purified prion stimulates the conversion of a purified heterologous protein into a prion form, suggests that facilitation of de novo prion formation by heterologous prions in vivo is a result of a direct interaction between the prion proteins (a cross-seeding mechanism) and does not require other cellular components. However, other cellular structures, e.g., the cytoskeleton, may provide a scaffold for these interactions in vivo and chaperones can further facilitate or inhibit this process. Some negative prion-prion interactions may also occur via a direct interaction between the prion proteins. Another explanation is a competition between the prions for cellular factors involved in prion propagation or differential effects of chaperones stimulated by one prion on the heterologous prions.

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Protein Misfolding and Amyloid Formation for the Peptide GNNQQNY from Yeast Prion Protein Sup35: Simulation by Reaction Path Annealing

Cited by 65 publications

References 43 publications

Direct Observation of Protein Folding, Aggregation, and a Prion-like Conformational Conversion

Direct Observation of Protein Folding, Aggregation, and a Prion-like Conformational Conversion

Dynamics of locking of peptides onto growing amyloid fibrils

Prion-Prion Interactions

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