Network of hotspot interactions cluster tau amyloid folds

Mullapudi, Vishruth; Vacquer-Alicea, Jaime; Bommareddy, Vaibhav; Vega, Anthony R.; Ryder, Bryan D.; White, Charles L.; Diamond, Marc I.; Joachimiak, Łukasz A.

doi:10.1101/2022.07.01.498342

Cited by 5 publications

(12 citation statements)

References 63 publications

(5 reference statements)

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“…We next interpreted the putative stability of these interactions. We leveraged a recently described computational method that captures the energetic contribution of interactions in a fibril based on changes in calculated energy of the assembly following alanine substitution 42 . Application of this method allows us to begin interpreting which interactions are important in our fibril assembly.…”

Section: Resultsmentioning

confidence: 99%

“…While our understanding of how these different fibrillar shapes are formed remains unknown, more general rules have emerged. We have found that the core amyloid motif interactions are modular in the ex vivo structures followed by more peripheral secondary interactions 42 . In the present work, we demonstrate a new way dysregulate local structures and promote amyloid motif exposure using lysine acetylation, which promotes gain-of-function interactions.…”

Section: Design Of Tau Elements To Regulate Tau Aggregationmentioning

confidence: 87%

“…In the structures we also see that lysine residues are inhibitory to tau aggregation – evidence that acetylation can promote peptide assembly into fibrils faster. In disease, lysine residues are often expose and do not contribute to the stability of fibrils 42 again indicating that under normal conditions they are protective but reorienting them through polyanion binding may preferentially expose the amyloid motifs to promote assembly.…”

Section: Discussionmentioning

confidence: 99%

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Disease-associated patterns of acetylation stabilize tau fibril formation

Nguyen

Mullapudi

et al. 2023

Preprint

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Assembly of the microtubule-associated protein into tauopathy fibril conformations dictates the pathology of a diversity of diseases. Recent cryogenic Electron Microscopy (cryo-EM) structures have uncovered distinct fibril conformations in different tauopathies but it remains unknown how these structures fold from a single protein sequence. It has been proposed that post-translational modifications may drive tau assembly but no direct mechanism for how modifications drive assembly has emerged. Leveraging established aggregation-regulating tau fragments that are normally inert, we tested the effect of chemical modification of lysines with acetyl groups on tau fragment conversion into amyloid aggregates. We identify specific patterns of acetylation that flank amyloidogenic motifs on the tau fragments that drive rapid fibril assembly. To understand how this pattern of acetylation may drive assembly, we determined a 3.9 Å cryo-EM structure of an amyloid fibril assembled from an acetylated tau fragment. The structure uncovers how lysine acetylation patterns mediate gain-of-function interactions to promote amyloid assembly. Comparison of the structure to an ex vivo tau fibril conformation from Picks Disease reveals regions of high structural similarity. Finally, we show that our lysine-acetylated sequences exhibit fibril assembly activity in cell-based tau aggregation assays. Our data uncover the dual role of lysine residues in limiting aggregation while their acetylation leads to stabilizing pro-aggregation interactions. Design of tau sequence with specific acetylation patterns may lead to controllable tau aggregation to direct folding of tau into distinct folds.

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Section: Resultsmentioning

confidence: 99%

Section: Design Of Tau Elements To Regulate Tau Aggregationmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

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Disease-associated patterns of acetylation stabilize tau fibril formation

Nguyen

Mullapudi

et al. 2023

Preprint

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“…We employed the Rosetta design module to computationally engineer the tau sequence using the CBD and PiD cryo-EM structures as templates (see methods) 33 . For the CBD fibril conformation, we optimized the 320 and 328 positions allowing sampling of all possible amino acid combinations yielding a matrix of 400 designed mutants.…”

Section: Computational Design Of Nonpolar Contacts Produces Spontaneo...mentioning

confidence: 99%

“…Changes in assembly energy were calculated using a method adapted from the Flex ddG protocol described by Barlow et. al 49 and more recently expanded for cryo-EM fibril assemblies 33 . From the input assembly, a set of pairwise atom constraints with a maximum distance of 9 Ang are generated with a weight of 1, using the fa_talaris2014 score function.…”

Section: Computational Design Of Tau Sequences Using Fibril Backbones...mentioning

confidence: 99%

FTD-tau S320F mutation stabilizes local structure and allosterically promotes amyloid motif-dependent aggregation

Chen

Wosztyl

Mullapudi

et al. 2022

Preprint

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Amyloid deposition of the microtubule-associated protein tau is a unifying theme in a multitude of neurodegenerative diseases. Disease-associated missense mutations in tau are associated with frontotemporal dementia (FTD) and enhance tau aggregation propensity. However, the molecular mechanism of how mutations in tau promote tau assembly into amyloids remains obscure. There is a need to understand how tau folds into pathogenic conformations to cause disease. Here we describe the structural mechanism for how an FTD-tau S320F mutation drives spontaneous aggregation. We use recombinant protein and synthetic peptide systems, computational modeling, cross-linking mass spectrometry, and cell models to investigate the mechanism of spontaneous aggregation of the S320F FTD-tau mutant. We discover that the S320F mutation drives the stabilization of a local hydrophobic cluster which allosterically exposes the 306VQIVYK311 amyloid motif. We identify a suppressor mutation that reverses the S320F aggregation phenotype through the reduction of S320F-based hydrophobic clustering in vitro and in cells. Finally, we use structure-based computational design to engineer rapidly aggregating tau sequences by optimizing nonpolar clusters in proximity to the S320 site revealing a new principle that governs the regulation of tau aggregation. We uncover a mechanism for regulating aggregation that balances transient nonpolar contacts within local protective structures or in longer-range interactions that sequester amyloid motifs. The introduction of a pathogenic mutation redistributes these transient interactions to drive spontaneous aggregation. We anticipate deeper knowledge of this process will permit control of tau aggregation into discrete structural polymorphs to aid design of reagents that can detect disease-specific tau conformations.

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FTD-tau S320F mutation stabilizes local structure and allosterically promotes amyloid motif-dependent aggregation

et al. 2023

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Amyloid deposition of the microtubule-associated protein tau is associated with neurodegenerative diseases. In frontotemporal dementia with abnormal tau (FTD-tau), missense mutations in tau enhance its aggregation propensity. Here we describe the structural mechanism for how an FTD-tau S320F mutation drives spontaneous aggregation, integrating data from in vitro, in silico and cellular experiments. We find that S320F stabilizes a local hydrophobic cluster which allosterically exposes the 306VQIVYK311 amyloid motif; identify a suppressor mutation that destabilizes S320F-based hydrophobic clustering reversing the phenotype in vitro and in cells; and computationally engineer spontaneously aggregating tau sequences through optimizing nonpolar clusters surrounding the S320 position. We uncover a mechanism for regulating tau aggregation which balances local nonpolar contacts with long-range interactions that sequester amyloid motifs. Understanding this process may permit control of tau aggregation into structural polymorphs to aid the design of reagents targeting disease-specific tau conformations.

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Network of hotspot interactions cluster tau amyloid folds

Cited by 5 publications

References 63 publications

Disease-associated patterns of acetylation stabilize tau fibril formation

Disease-associated patterns of acetylation stabilize tau fibril formation

FTD-tau S320F mutation stabilizes local structure and allosterically promotes amyloid motif-dependent aggregation

FTD-tau S320F mutation stabilizes local structure and allosterically promotes amyloid motif-dependent aggregation

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