Cross-seeding and Conformational Selection between Three- and Four-repeat Human Tau Proteins

Yu, Xiaoyan; Luo, Yin; Dinkel, Paul D.; Zheng, Jie; Wei, Guanghong; Margittai, Martin; Nussinov, Ruth; Ma, Buyong

doi:10.1074/jbc.m112.340794

Cited by 66 publications

(78 citation statements)

References 41 publications

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“…This is similar to the salt bridge distributions in K18 and K19 fibrils. 33 As shown in Supporting Information Figure S6a and b, the binding of tau protein to Aβ oligomer increases tau K18 and K19 residues exposed hydrophobic surface area, particularly the two nucleating segments ( 275 VQIINK 280 ) in R2 and ( 306 VQIVYK 311 ) in R3. Exposure of such mainly hydrophobic segments would facilitate the association of tau with these hydrophobic segments of a second tau monomer through hydrophobic interactions, leading to tau aggregation and nucleation.…”

Section: Lettermentioning

confidence: 88%

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Aβ “Stretching-and-Packing” Cross-Seeding Mechanism Can Trigger Tau Protein Aggregation

Luo

Wei

et al. 2015

J. Phys. Chem. Lett.

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There are synergistic effects of Aβ and tau protein in Alzheimer's disease. Aβ 1−42 protofibril seeds induce conversion of human tau protein into β-sheet-rich toxic tau oligomers. However, the molecular mechanisms underlying such a conformational conversion are unclear. Here, we use extensive all atom replica exchange molecular dynamics simulations to investigate the effects of preformed Aβ 1−42 protofibril on two monomeric tau constructs: K18 and K19. We found that Aβ oligomer stretches tau conformation and drastically reduces the metastable secondary structures/hydrogen bonding/salt-bridge networks in tau monomers and exposes their fibril nucleating motifs 275 VQIINK 280 and 306 VQIVYK 311 . Aβ interacting patches around Tyr10/Ile41 contribute significantly to the interactions with K18 and K19. Aβ cross-seeded tau aggregation can adopt a "stretching-and-packing" mechanism, paving the way for the next, prion-like growth step. The results provide a mechanism on the atomic level to experimental observations that tau pathogenesis is promoted by Aβ 1−42 but not by Aβ 1−40 .A myloid β (Aβ) forms extracellular senile plaques and tau protein simultaneously forms intracellular neurofibrillary tangles (NFTs) in the brain of Alzheimer's disease patients. 1,2 There is increasing evidence of independent and synergistic effects of Aβ and tau. 3−5 Classically, Aβ and tau are respectively deposited extra-and intracellularly. However, Aβ also accumulates intraneuronally 2,6 and it binds to tau to form insoluble complexes within the same neurons. 7 In the Aβ-induced tau pathology, Aβ accumulation occurs prior to tau in AD pathogenesis and triggers the conversion of tau from normal to toxic states. 3,4,6,8−15 Although mechanisms linking Aβ and tau-pathology have not been conclusively identified, several potential mechanisms have been postulated. These posit that (1) Aβ interacts directly with neuronal receptors and membranes, (2) Aβ induces inflammation via glial cells, and (3) Aβ directly seeds and propagates tau aggregation. 4 The third mechanism has recently drawn increasing attention. 4,8,16−18 Propagation of toxic, misfolded Aβ and tau bears a striking resemblance to that of the prion protein. 16,17,19 Misfolded Aβ promotes tau aggregation in vitro through direct, intermolecular interaction. 15,20,21 Intriguingly, injection of preaggregated synthetic amyloid peptides 9 or aggregated amyloid peptide enriched brain extracts 22 induced tau aggregation not only at the injection site but also in functionally connected brain regions remote from the site, which indicates that amyloid peptides can initiate and propagate tau aggregation in these regions as well. 9,22 This prion-like behavior 23,24 of Aβ and tau underscores the need for an in-depth understanding of the seeding mechanism through which Aβ induces tau pathology.It has been shown that Aβ 1−42 oligomer seeds induce the conversion of unstructured, monomeric human recombinant tau into β-sheet-rich toxic tau oligomers. 20 Previous simulations of the interactions of Aβ fibri...

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Section: Lettermentioning

confidence: 88%

“…These observations are consistent with previous studies of crossseeding between K18 and K19. 32,33 R2 is the dominant K18 repeat. Because it is missing in K19, K18 cannot seed K19.…”

mentioning

confidence: 99%

Aβ “Stretching-and-Packing” Cross-Seeding Mechanism Can Trigger Tau Protein Aggregation

Luo

Wei

et al. 2015

J. Phys. Chem. Lett.

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“…Both amyloid seeds from hIAPP and Aβ peptides could serve as the interacting precursors to mutually promote the amyloid elongation. Consistently, a number of studies have reported that amyloids from different species or with different sequences can overcome cross-seeding barriers to form cross-seeding aggregates and fibrils via the elongation pathway if they have close structural similarity, including tau-k18 and tau-k19 [84][85][86][87] , Aβ and tau 29 , and hIAPP and rIAPP 25 . Meanwhile, it is interesting to note that the tail-tail model also had a relatively higher population of 21.1%.…”

Section: Structural Populations Of Polymorphic Aβ-hiapp Assembliesmentioning

confidence: 79%

Polymorphic Associations and Structures of the Cross-Seeding of Aβ_1–42 and hIAPP_1–37 Polypeptides

Zhang¹,

Hu²,

Chen³

et al. 2015

J. Chem. Inf. Model.

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Emerging evidence have shown that the patients with Alzheimer's disease (AD) often have a higher risk of later developing type II diabetes (T2D), and vice versa, suggesting a potential pathological link between AD and T2D. Amyloid-β (Aβ) and human islet amyloid polypeptide (hIAPP) are the principle causative components responsible for the pathologies of AD and T2D, respectively. The cross-sequence interactions between Aβ and hIAPP may provide a molecular basis for better understanding the potential link between AD and T2D. Herein, we systematically modeled and simulated the cross-sequence aggregation process, molecular interactions, and polymorphic structures of full-length Aβ and hIAPP peptides using a combination of coarse-grained (CG) replica-exchange molecular dynamics (REMD) and all-atom molecular dynamics (MD) simulations, with particular focus on the effect of association models between Aβ and hIAPP on the structural stability and polymorphic populations of hybrid Aβ-hIAPP aggregates. Four distinct association models (double-layer, elongation, tail-tail, and block models) between Aβ and hIAPP oligomers were identified, and the associated polymorphic Aβ-hIAPP structures were determined as well. Among them, different association models led to different Aβ-hIAPP aggregates, with large differences in structural morphologies and populations, interacting interfaces, and underlying association forces. The computational models support the cross-sequence interactions between Aβ and hIAPP pentamers, which would lead to the complex hybrid Aβ-hIAPP assemblies. This computational work may also provide a different point of view to a better understanding of a potential link between AD and T2D.

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“…The PHFs can get through the adjacent cells, then induce fibrillization of intracellular human Tau in these naive recipient cells via direct protein-protein contact [43,44]. The filaments can form not only by the full-length human Tau protein, but also by the three repeated or four repeated Tau segments, and there is cross-seeding and conformational selection between both Tau segments [45]. Following a similar paradigm, intracerebral injection of mutant Tau aggregate-containing brain extracts can cause widespread aggregation of normal human Tau in transgenic mice that do not otherwise develop aggregates [46,47], and aggregated Tau can initiate neurofibrillary tangle formation in vivo [48].…”

Section: Prion-like Protein Aggregation: Tau Protein Aggregationmentioning

confidence: 99%

Recent progress in prion and prion-like protein aggregation

Yi¹,

Xu²,

Chen³

et al. 2013

ABBS

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Prion diseases and prion-like protein misfolding diseases involve the accumulation of abnormally aggregated forms of the normal host proteins, such as prion protein and Tau protein. These proteins are special because of their self-duplicating and transmissible characteristics. Such abnormally aggregated proteins mainly formed in neurons, cause the neurons dysfunction, and finally lead to invariably fatal neurodegenerative diseases. Prion diseases appear not only in animals, such as bovine spongiform encephalopathy in cattle and scrapie in sheep, but also in humans, such as Creutzfeldt -Jacob disease, and even the same prion or prion-like proteins can have many different phenotypes. A lot of biological evidence has suggested that the molecular basis for different strains of prions could be hidden in protein conformations, and the misfolded proteins with conformations different from the normal proteins have been proved to be the main cause for protein aggregation. Crowded physiological environments can be imitated in vitro to study how the misfolding of these proteins leads to the diseases in vivo. In this review, we provide an overview of the existing structural information for prion and prion-like proteins, and discuss the post-translational modifications of prion proteins and the difference between prion and other infectious pathogens. We also discuss what makes a misfolded protein become an infectious agent, and show some examples of prion-like protein aggregation, such as Tau protein aggregation and superoxide dismutase 1 aggregation, as well as some cases of prion-like protein aggregation in crowded physiological environments.

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Cross-seeding and Conformational Selection between Three- and Four-repeat Human Tau Proteins

Cited by 66 publications

References 41 publications

Aβ “Stretching-and-Packing” Cross-Seeding Mechanism Can Trigger Tau Protein Aggregation

Aβ “Stretching-and-Packing” Cross-Seeding Mechanism Can Trigger Tau Protein Aggregation

Polymorphic Associations and Structures of the Cross-Seeding of Aβ_1–42 and hIAPP_1–37 Polypeptides

Recent progress in prion and prion-like protein aggregation

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Cross-seeding and Conformational Selection between Three- and Four-repeat Human Tau Proteins

Cited by 66 publications

References 41 publications

Aβ “Stretching-and-Packing” Cross-Seeding Mechanism Can Trigger Tau Protein Aggregation

Aβ “Stretching-and-Packing” Cross-Seeding Mechanism Can Trigger Tau Protein Aggregation

Polymorphic Associations and Structures of the Cross-Seeding of Aβ1–42 and hIAPP1–37 Polypeptides

Recent progress in prion and prion-like protein aggregation

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Product

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Polymorphic Associations and Structures of the Cross-Seeding of Aβ_1–42 and hIAPP_1–37 Polypeptides