Alzheimer's Disease Amyloid Propagation by a Template-Dependent Dock-Lock Mechanism

Esler, William P.; Stimson, Evelyn R.; Jennings, Joan; Vinters, Harry V.; Ghilardi, Joseph R.; Lee, Jonathan P.; Mantyh, and Patrick W.; Maggio, John E.

doi:10.1021/bi992933h

Cited by 348 publications

(474 citation statements)

References 26 publications

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“…Amyloid growth has been described in terms of a two state "Dock and Lock" process based on distinct populations observed in dissociation experiments. 46 In these experiments the defining feature of the docked state is that it can reversibly unbind from the fibril. Therefore, in the present theory the docked state can be identified with mis-aligned polypeptides and the locked state with the correctly bound molecules.…”

Section: Discussionmentioning

confidence: 99%

Kinetic theory of amyloid fibril templating

Schmit

2013

The Journal of Chemical Physics

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The growth of amyloid fibrils requires a disordered or partially unfolded protein to bind to the fibril and adapt the same conformation and alignment established by the fibril template. Since the H-bonds stabilizing the fibril are interchangeable, it is inevitable that H-bonds form between incorrect pairs of amino acids which are either incorporated into the fibril as defects or must be broken before the correct alignment can be found. This process is modeled by mapping the formation and breakage of H-bonds to a one-dimensional random walk. The resulting microscopic model of fibril growth is governed by two timescales: the diffusion time of the monomeric proteins, and the time required for incorrectly bound proteins to unbind from the fibril. The theory predicts that the Arrhenius behavior observed in experiments is due to off-pathway states rather than an on-pathway transition state. The predicted growth rates are in qualitative agreement with experiments on insulin fibril growth rates as a function of protein concentration, denaturant concentration, and temperature. These results suggest a templating mechanism where steric clashes due to a single mis-aligned molecule prevent the binding of additional molecules.

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Section: Discussionmentioning

confidence: 99%

Kinetic theory of amyloid fibril templating

Schmit

2013

The Journal of Chemical Physics

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“…Indeed, although the early interactions between either dispersed Ure2p molecules or that and nuclei ends can be reversible, a late conformational rearrangement that may be limited to the flexible N-terminal region of the protein could lock Ure2p molecules that are docked to fibril ends into the fibrillar form, thus disabling individual Ure2p molecules to fluctuate between two states, dispersed molecules and polymers. Such a "dock-lock" mechanism has been shown to occur upon assembly of human ␤-amyloid peptide into fibrils (36) and has been proposed to account for the irreversible aggregation of PrP (prion protein) (37). Thus, the practically irreversible assembly process of Ure2p into fibrils akin to the aggregation of PrP (prion protein) could be a general and common trait of prion proteins constituting an essential component of the molecular processes at the origin of prion propagation.…”

Section: Discussionmentioning

confidence: 99%

Assembly of the Yeast Prion Ure2p into Protein Fibrils

Fay

Inoue

Bousset

et al. 2003

Journal of Biological Chemistry

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The [URE3] phenotype in Saccharomyces cerevisiaepropagates by a prion mechanism, involving the aggregation of the normally soluble and highly helical protein Ure2. Previous data have shown that the protein spontaneously forms in vitro long, straight, insoluble fibrils at neutral pH that are similar to amyloids in that they bind Congo red and show green-yellow birefringence and have an increased resistance to proteolysis. These fibrils are not amyloids as they are devoid of a cross-␤ core. Here we further document the mechanism of assembly of Ure2p into fibrils. The critical concentration for Ure2p assembly is measured, and the minimal size of the nuclei that are the precursors of Ure2p fibrils is determined. Our data indicate that the assembly process is irreversible. As a consequence, the critical concentration is very low. By analyzing the elongation rates of preformed fibrils and combining the results with singlefiber imaging experiments of a variant Ure2p labeled by fluorescent dyes, we reveal the polarity of the fibrils and differences in the elongation rates at their ends. These results bring novel insight in the process of Ure2p assembly into fibrils and the mechanism of propagation of yeast prions.Creutzfeldt-Jacob disease, bovine spongiform encephalopathy, and sheep scrapie are transmissible spongiform encephalopathies. They are believed to be caused by a constitutive protein called prion protein (PrP) in an altered conformation (1). This rare form of the protein is thought to convert the normal form to the infectious conformation in a catalytic manner (for review, see Ref.2). The molecular events at the origin of propagation are not yet elucidated. In the lower eukaryotes Saccharomyces cerevisiae and Podospora anserina prion proteins have been identified taking advantage of traits they confer (3-7). These proteins are harmless for humans and constitute valuable model systems to characterize prion propagation.The [URE3] phenotype in S. cerevisiae is caused by a disorder in a signal transduction cascade that regulates nitrogen catabolism (8). Yeast cells exhibiting the [URE3] phenotype have the ability to take up ureidosuccinate, the structural analogue of allantoate, a poor nitrogen source in the presence of a good nitrogen source such as ammonium ions. This is believed to be because of the loss of the function of the protein determinant of [URE3], Ure2p, whose function is unknown although reported to be involved in yeast heavy metal and strong oxidant detoxification (9). Importantly, Ure2p [URE3] promotes the conversion of the newly synthesized active Ure2p into an inactive form. Thus, the Ure2p [URE3] state is heritable, independent of any nucleic acid (10).Native soluble Ure2p assembles in vitro into fibrils that exhibit the characteristics of amyloids in that they are about 20 nm wide and more than 1 m long, bind thioflavin T and Congo Red, show yellow-green birefringence in polarized light upon Congo Red binding, and exhibit an increased resistance to proteolysis (11-13). The assembly reaction fo...

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“…Upon forming N n * ͑with n Ͼ the size of the critical nucleus n c ͒, S monomers can rapidly add to the oligomer resulting in their growth and eventual fibril assembly. The templated-assembly ͑TA͒ process [28][29][30] suggests that preformed N n * complex, with presumably n Ͼ n c , serves as a template onto which S or N * can dock and undergo the needed structural rearrangement to lock onto the template. Based on kinetic data on prion formation in yeasts, the nucleated conformational conversion ͑NCC͒ model 1,31 has been proposed.…”

Section: Introductionmentioning

confidence: 99%

Probing the mechanisms of fibril formation using lattice models

Klimov²,

Straub

et al. 2008

The Journal of Chemical Physics

114

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Using exhaustive Monte Carlo simulations we study the kinetics and mechanism of fibril formation using lattice models as a function of temperature ͑T͒ and the number of chains ͑M͒. While these models are, at best, caricatures of peptides, we show that a number of generic features thought to govern fibril assembly are captured by the toy model. The monomer, which contains eight beads made from three letters ͑hydrophobic, polar, and charged͒, adopts a compact conformation in the native state. In both the single-layered protofilament ͑seen for M ഛ 10͒ and the two-layer fibril ͑M Ͼ 10͒ structures, the monomers are arranged in an antiparallel fashion with the "strandlike" conformation that is perpendicular to the fibril axis. Partial unfolding of the folded monomer that populates an aggregation prone conformation ͑N * ͒ is required for ordered assembly. The contacts in the N * conformation, which is one of the four structures in the first "excited" state of the monomer, are also present in the native conformation. The time scale for fibril formation is a minimum in the T-range when the conformation N * is substantially populated. The kinetics of fibril assembly occurs in three distinct stages. In each stage there is a cascade of events that transforms the monomers and oligomers to ordered structures. In the first "burst" stage, highly mobile oligomers of varying sizes form. The conversion to the N * conformation occurs within the oligomers during the second stage in which a vast number of interchain contacts are established. As time progresses, a dominant cluster emerges that contains a majority of the chains. In the final stage, the aggregation of N * particles serve as a template onto which smaller oligomers or monomers can dock and undergo conversion to fibril structures. The overall time for growth in the latter stages is well described by the LifshitzSlyazov growth kinetics for crystallization from supersaturated solutions. The detailed analysis shows that elements of the three popular models, namely, nucleation and growth, templated assembly, and nucleated conformational conversion are present at various stages of fibril assembly.

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Alzheimer's Disease Amyloid Propagation by a Template-Dependent Dock-Lock Mechanism

Cited by 348 publications

References 26 publications

Kinetic theory of amyloid fibril templating

Kinetic theory of amyloid fibril templating

Assembly of the Yeast Prion Ure2p into Protein Fibrils

Probing the mechanisms of fibril formation using lattice models

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