14 Feb 2020
Evidence continues to pile up that filaments of aggregated tau form unique strains in different tauopathies. Why is that? A paper in the February 20 Cell suggests that post-translational modifications help decide a filaments ultimate shape. Investigators led by Anthony Fitzpatrick, Columbia University, New York, paired cryo-electron microscopy images of tau filaments from people with corticobasal degeneration (CBD) and Alzheimers disease with mass spectrometry to identify amino acid adducts. They report unique modifications in the protofibril of each structure.
The powerful combination of cryo-EM with mass spectrometry gives a more complete representation of the aggregated tau protein as it actually exists in the diseased brain, said Lary Walker, Emory University, Atlanta.
Cryo-EM alone yields important insights into the core structure of tau tangles, but precisely localizing post-translational modifications adds flesh to the bones, he said.
Meanwhile, scientists led by Sjors Scheres and Michel Goedert at the MRC Laboratory of Molecular Biology in Cambridge, England, U.K., also used cryo-EM to resolve the structure of CBD fibrils. In the February 12 Nature, they report a mysterious molecule hiding in a fold in the protofibril, much like they found in tau protofibrils from a person with chronic traumatic encephalopathy. Fitzpatricks group found a similar molecule. Scheres does not believe this is a post-translational modification because it does not seem covalently attached. Together, the two papers offer the first high-resolution view of tau fibrils in CBD.
Tau Doublet. CBD tau protofibrils comprise two monomers joined back-to-back. Each C-shaped monomer comprises 107 amino acids (circles), that form 11 -sheets (solid black lines). Non-tau moieties (pink) lie trapped within the fold or are covalently connected to the outside. [Courtesy of Arakhamia et al., 2020.]
In recent years, Scheres, Goedert, and colleagues have been methodically resolving the structures of tau filaments found in various tauopathies. They found that paired helical filaments and straight fibrils of tau from AD brain contained the same C-shaped protofibril structure (Jul 2017 news). Protofibrils in tau filaments from Picks disease and chronic traumatic encephalopathy assumed different J- and C-shaped structures (Aug 2018 news; Mar 2019). No one had yet examined filaments from CBD, which form from a tau isoform containing all four microtubule-binding domains. Tau can be alternatively spliced to have either three (3R) or four (4R) of these repeats. Fibrils in Picks disease incorporate only 3R tau, those in both AD and CTE have 3R and 4R forms.
Previous structural analyses of tau fibrils with cryo-EM focused on its fibril-forming core. To isolate that, researchers used the enzyme pronase to remove the fuzzy outer coat of the fibril, revealing the more stable interior of the filament. However, pronase can strip away post-translational modifications as well, and tau accrues a whole host of them, some being disease-dependent (Jul 2015 news; Sep 2015 news). The group wondered if these alterations explain the unique structures of fibrils found in different tauopathies.
To find out, co-first authors Tamta Arakhamia, Christina Lee, and Yari Carlomagno used cryo-EM to examine the undigested tau fibrils taken postmortem from the brain of a person with CBD. As has been reported previously, the sarkosyl-insoluble material was made up of both twisted and straight filaments (Ksiezak-Reding et al., 1996). The former was twice as wide and abundant as the latter.
The two fibrils were made of the same conformer of misfolded tau. While straight fibrils comprised just one column of monomers, each rung of the twisted fibril consisted of a linked pair (see image above). For both, the core-forming protofibril spanned amino acids 274 to 380. It included the last residue of R1, all of R2, R3, and R4, and 12 residues after R4. These regions formed 11 -sheetsthree from R2, three from R3, four from R4, and one formed by the last 13 amino acids. The sheets folded into four layers, forming a C-shaped loop (see image above).
Scheres and Goedert also analyzed undigested CBD tau fibrils using cryo-EM. First author Wenjuan Zhang and colleagues found essentially the same -sheet configuration and fold as did Fitzpatrick and colleagues. Zhang also found a molecule inside the fold of the protofibril. It was not covalently attached to any amino acid. Based on the positively charged amino acids that surround it, Zhang predicted this molecule to have a net negative charge of -3, and be 4 x 9 ngstroms in size. Scheres had reported a similarly mysterious molecule inside the fold of CTE protofibrils, but that one was hydrophobic.
Arakhamia also found a large density inside the molecule, deep within a hydrophilic cavity formed by amino acids 281296 and 358374. It was not covalently bound, and so does not appear to be an amino acid modification. However, they found other large, non-tau densities adorning the outside of the fibrils. On the straight fibrils, these were attached to lysines 321, 343, 353, and 369, and to one histidine, H362. On the twisted form, they linked to K321, K353, and H362.
To identify these non-tau densities, Arakhamia and co-authors analyzed fibrils from several people with CBD by mass spectrometry, then mapped the identified PTMs onto the cryo-EM structure (see image below). The authors found numerous phospho, trimethyl, acetyl, and ubiquitin additions. Some amino acids were either acetylated or ubiquitinated. Strikingly, while a few phospho groups attached to the superficial fuzzy outer coat, acetyl and ubiquitin groups predominated in the fibril-forming core.
PTM Map. Mass spectrometry identified modifications on amino acid sidechains of tau monomers from CBD (left) and AD (right). For the most part, acetylation (blue), ubiquitination (orange), and trimethylation (red) modified the fibril-forming cores, while phosphorylation (green) took place outside. [Courtesy of Arakhamiaet al., 2020.]
I found that to be surprising, said Li Gan, Weill Cornell Medicine, New York. I would have assumed that the tau fibrils in the diseased brain would be hyperphosphorylated.
Do these modifications affect folding of tau fibrils? That acetyl and ubiquitin groups bound to the core suggested to the authors that these were present as tau fibrils formed and played a hand in their aggregation. Acetylation may make tau protein less soluble, as it neutralizes positive charges on side chains and reduces their repulsion, predicted the authors. Ubiquitin may stabilize stacks of -sheets by providing more surfaces for hydrogen bonding. Likewise, Zhang and colleagues think the mysterious hydrophilic molecule inside the fold might also be important in formation of the filament. That it is buried inside each monomer suggests that it is continuously incorporated during fibrillization and may stabilize the CBD fold during filament assembly, they wrote.
Could modifications of tau dictate which type of fold, and therefore which strain, accumulates in the brains of different diseases? Arakhamia and colleagues compared CBD tau PTMs with those on tau fibrils from AD. Again, they mapped mass spectrometry data from many fibrils onto the cryoEM structure. As in the CBD fibril, phosphoryl groups attached mainly beyond the protofibril core of AD tau, while acetyl and ubiquitin groups bound to the core. However, the amino acids modified were different in the different protofibrils and in the filaments they formed. In CBD, ubiquitinated K353 and acetylated K343 were found in twisted fibrils. The reverse, acetylated K353 and ubiquitinated K343, modified straight filaments. Similarly, acetyl groups bound K311 and K317/K321 in AD paired helical filaments, but ubiquitin occupies each of those sidechains in straight filaments. The results hint that PTMs influence the shape of aggregating tau fibrils.
This finding implies that ubiquitin ligases and acetyltransferases modulate the behavior of tau, potentially tuning the ratio of fibril subtypes in tau inclusions, Fitzpatrick wrote to Alzforum. It will be informative to use our approach of combining cryo-EM with PTM mapping by mass spectrometry to determine the additional structural role played by PTMs in tau oligomer formation and template-based seeding.
This paper illustrates, on a single-molecule level, that the interplay between acetylation and ubiquitination could play a role in tau fibrillization and strain properties, Gan told Alzforum. If PTMs play such an important role in fibril formation, the recombinant seeds people have been using may not be as biologically relevant, she added. Goedert emphasized this at the Tau2020 meeting held in Washington, D.C., February 1213. He noted that tau structures formed from recombinant protein using heparin are different from those isolated from brain tissue, particularly with respect to the fourth repeat and the 12 amino acids that come after it. Cryo-EM findings cast a lot of doubt on work using recombinant tau structures, he said.
Gan noted that the physiological consequences of the different tau strainsor whether they are even toxicis unclear. Before we develop strain-specific approaches, we need to understand what the strains do. On that note, Marc Diamond, UT Southwestern Medical Center, Dallas, wondered whether PTMs were causal or incidental. He suggested that researchers find out by removing PTMs from fibrils before seeding. If that does not change the strain output, it would imply that they were not required for strain identity.Gwyneth Dickey Zakaib
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CryoEM of CBD Tau Suggests Another Unique Protofibril - Alzforum
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