Tau R2 and R3 are essential regions for tau aggregation, seeding and propagation

Annadurai, Narendran; Malina, Lukáš; Malohlava, Jakub; Hajdúch, Marián; Das, Viswanath

doi:10.1016/j.biochi.2022.05.013

Cited by 11 publications

(19 citation statements)

References 42 publications

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“…Of the segments identified as potentially forming amyloids, we argue on the bases of structural and evolutionary constraints that two of them in the T domain are likely to function in vivo. We note that Als5 might have main and minor aggregation sites, with the latter taking over in case of interference or mutation in the main site, as previously suggested for Tau involved in Alzheimer's disease and for Fap amyloids involved in the biofilm of Pseudomonas (Christensen et al, 2019;Annadurai et al, 2022). We also showed atomic-level cross-β spine structures with known and novel geometries, including one LARKS-like structure reminiscent of functional and reversible human amyloids (Guenther et al, 2018;Hughes et al, 2018).…”

Section: Discussionsupporting

confidence: 71%

Structure and Conservation of Amyloid Spines From the Candida albicans Als5 Adhesin

Golan

Schwartz-Perov

Landau

et al. 2022

Front. Mol. Biosci.

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Candida Als family adhesins mediate adhesion to biological and abiotic substrates, as well as fungal cell aggregation, fungal-bacterial co-aggregation and biofilm formation. The activity of at least two family members, Als5 and Als1, is dependent on amyloid-like protein aggregation that is initiated by shear force. Each Als adhesin has a ∼300-residue N-terminal Ig-like/invasin region. The following 108-residue, low complexity, threonine-rich (T) domain unfolds under shear force to expose a critical amyloid-forming segment 322SNGIVIVATTRTV334 at the interface between the Ig-like/invasin domain 2 and the T domain of Candida albicans Als5. Amyloid prediction programs identified six potential amyloidogenic sequences in the Ig-like/invasin region and three others in the T domain of C. albicans Als5. Peptides derived from four of these sequences formed fibrils that bound thioflavin T, the amyloid indicator dye, and three of these revealed atomic-resolution structures of cross-β spines. These are the first atomic-level structures for fungal adhesins. One of these segments, from the T domain, revealed kinked β-sheets, similarly to LARKS (Low-complexity, Amyloid-like, Reversible, Kinked segments) found in human functional amyloids. Based on the cross-β structures in Als proteins, we use evolutionary arguments to identify functional amyloidogenic sequences in other fungal adhesins, including adhesins from Candida auris. Thus, cross-β structures are often involved in fungal pathogenesis and potentially in antifungal therapy.

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Section: Discussionsupporting

confidence: 71%

Structure and Conservation of Amyloid Spines From the Candida albicans Als5 Adhesin

Golan

Schwartz-Perov

Landau

et al. 2022

Front. Mol. Biosci.

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“…We have recently shown that R2 and R3 cause a time- and dose-dependent increase in total- and pSer262- tau levels in triton-insoluble fractions of induced cells [28]. In addition, we have also shown that the presence of P301S mutation in biosensor cells enhanced pSer262 tau even in triton-soluble fractions, and P301S Tau is prone to aggregate into insoluble fractions upon exposure to exogenous R2 and R3 fibrils [27,28]. The pSer262-containing intracellular aggregates in R2 and R3-induced cells were also seed-competent [27].…”

Section: Resultsmentioning

confidence: 99%

“…Cells expressing P301L-tau have been shown to escape all three types of autophagy, such as macroautophagy, chaperone-mediated autophagy, and endosomal microautophagy-mediated degradation [18]. In addition, we have recently shown the enhanced conversion of soluble phosphorylated Ser262 tau into insoluble inclusions in R2 and R3-induced P301S-tau expressing cells [27,28]. In this study, we show that intracellular phosphorylated tau inclusions in R2- and R3-induced cells resist the aggregate-clearing mechanism and that failed autophagy is one of the mechanisms responsible for intracellular accumulation of aggregates.…”

Section: Discussionmentioning

confidence: 99%

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Differential seeding by exogenous R2 and R3 fibrils influences autophagic degradation of intracellular tau aggregates in Tau K18 P301S cells

Annadurai,

Kubíčková,

Frydrych

et al. 2023

Preprint

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Aggregation of misfolded tau protein is a common feature of tauopathies. Cells employ diverse mechanisms to eliminate misfolded tau with different conformations, contributing to the varied clinical and pathological manifestations of tauopathies. This study focuses on the clearance of seeded tau aggregates following the induction of biosensor cells with R2 and R3 fibrils that exhibit distinct aggregation kinetics and seeding potencies. Our hypothesis is that the dissimilarity in time-dependent intracellular seeding induced by R2 and R3 fibrils underlies the variation in autophagy failure. These discrepancies may account for the heterogeneity of pathology and disease progression between 3R and 4R tauopathies, given the absence of R2 in 3R tau isoforms. In R2-induced cells, alterations in p62 and LC3II/I levels, indicative of proteotoxic stress and autophagy failure, occur sooner than in R3-induced cells. Conversely, LAMP1 levels remained unaffected, suggesting a failure in the fusion of aggregate-containing autophagosomes with lysosomes. This autophagic failure may increase seed-dependent intracellular aggregation in induced cells. Consequently, we assessed the impact of autophagy inducers on the clearance of intracellular tau aggregates in induced cells. Epigallocatechin gallate (EGCG) demonstrated the highest efficacy in inducing autophagy and reducing p62 levels, decreasing seeding and clearing aggregates. Overall, this study elucidates the differential effects of prion-like R2 and R3 strains on autophagy and highlights how compounds like EGCG can selectively reduce tau aggregation to treat specific tauopathies. We provide insights into the distinct mechanisms of autophagy failure and autophagy clearance of intracellular aggregates in cells induced with R2 and R3 fibrils.

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“…Their inability to seed naïve tau into aggregates suggests an additional sequence is required for transcellular spread of misfolded tau in a prion-like manner. Inroads to this problem have emerged with the introduction of longer peptides that extend the 6-mer amyloidogenic core to include portions of the tau repeat 2 and 3 sequences 16,20,56,57 . This report defines a 19 amino acid peptide designated jR2R3 P301L that spans the 2R-3R junction and is capable of forming fibrillar structures.…”

Section: Discussionmentioning

confidence: 99%

Precision Proteoform Design for 4R Tau Isoform Selective Templated Aggregation

Longhini,

DuBose,

Lobo

et al. 2023

Preprint

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Prion-like spread of disease-specific tau conformers is a hallmark of all tauopathies. We used a 19-residue probe peptide spanning the R2/R3 splice junction of tau to induce aggregation specifically of 4R, but not 3R tau. The aggregates can propagate as isoform-specific seeds over multiple generations, have a high β-sheet content, a lipid signal, and resemble the PSP cryo-EM fold. A simulation of peptide free energy landscapes pinpointed the features of the hairpin structure uniquely found in the cryo-EM structures of pure 4R tauopathies and captured in the peptide. These molecular dynamic simulations were experimentally validated by the S305K substitution in 4R tau, corresponding to the position found in 3R tau. This single amino acid substitution prevented tau aggregates induced by the prion-like probe peptide. The tau aggregates were dynamic and displayed growth, stability, and shrinking over time. These results could serve as the basis for tau isoform-specific therapeutic interventions.

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Tau R2 and R3 are essential regions for tau aggregation, seeding and propagation

Cited by 11 publications

References 42 publications

Structure and Conservation of Amyloid Spines From the Candida albicans Als5 Adhesin

Structure and Conservation of Amyloid Spines From the Candida albicans Als5 Adhesin

Differential seeding by exogenous R2 and R3 fibrils influences autophagic degradation of intracellular tau aggregates in Tau K18 P301S cells

Precision Proteoform Design for 4R Tau Isoform Selective Templated Aggregation

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