Automated model building and protein identification in cryo-EM maps

Nature, Journal Year: 2024, Volume and Issue: 628(8007), P. 450 - 457

Published: Feb. 26, 2024

Interpreting electron cryo-microscopy (cryo-EM) maps with atomic models requires high levels of expertise and labour-intensive manual intervention in three-dimensional computer graphics programs

Language: Английский

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Amyloid nomenclature 2022: update, novel proteins, and recommendations by the International Society of Amyloidosis (ISA) Nomenclature Committee

Amyloid, Journal Year: 2022, Volume and Issue: 29(4), P. 213 - 219

Published: Oct. 2, 2022

The Nomenclature Committee of the International Society Amyloidosis met at XVIII Symposium on in September and virtually October 2022 with discussions resulting this upgraded nomenclature recommendation. principles remain unchanged but there is an ongoing discussion regarding importance varying nature intracellular protein aggregates, particularly those associated neurodegenerative diseases. Six novel proteins were added to list human amyloid fibril proteins. Of these, three are polypeptide hormones two currently utilised peptide drugs, making number known iatrogenic forms four, all appearing as subcutaneous nodules injection site. sixth transmembrane 106B protein, forming fibrils disorders frontotemporal dementia. now 42.

Language: Английский

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Molecular pathology of neurodegenerative diseases by cryo-EM of amyloids

Nature, Journal Year: 2023, Volume and Issue: 621(7980), P. 701 - 710

Published: Sept. 27, 2023

Language: Английский

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TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry

Cell, Journal Year: 2023, Volume and Issue: 186(16), P. 3427 - 3442.e22

Published: July 7, 2023

SARS-CoV-2 is associated with broad tissue tropism, a characteristic often determined by the availability of entry receptors on host cells. Here, we show that TMEM106B, lysosomal transmembrane protein, can serve as an alternative receptor for into angiotensin-converting enzyme 2 (ACE2)-negative Spike substitution E484D increased TMEM106B binding, thereby enhancing TMEM106B-mediated entry. TMEM106B-specific monoclonal antibodies blocked infection, demonstrating role in viral Using X-ray crystallography, cryogenic electron microscopy (cryo-EM), and hydrogen-deuterium exchange mass spectrometry (HDX-MS), luminal domain (LD) engages receptor-binding motif spike. Finally, promotes spike-mediated syncytium formation, suggesting fusion. Together, our findings identify ACE2-independent infection mechanism involves cooperative interactions heparan sulfate TMEM106B.

Language: Английский

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Automated model building and protein identification in cryo-EM maps

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: May 16, 2023

Interpreting electron cryo-microscopy (cryo-EM) maps with atomic models requires high levels of expertise and labour-intensive manual intervention. We present ModelAngelo, a machine-learning approach for automated model building in cryo-EM maps. By combining information from the map protein sequence structure single graph neural network, ModelAngelo builds proteins that are similar quality as those generated by human experts. For nucleotides, backbones accuracy humans. using its predicted amino acid probabilities each residue hidden Markov searches, outperforms experts identification unknown sequences. will thus remove bottlenecks increase objectivity determination.

Language: Английский

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TDP-43 forms amyloid filaments with a distinct fold in type A FTLD-TDP

Nature, Journal Year: 2023, Volume and Issue: 620(7975), P. 898 - 903

Published: Aug. 2, 2023

Abstract The abnormal assembly of TAR DNA-binding protein 43 (TDP-43) in neuronal and glial cells characterizes nearly all cases amyotrophic lateral sclerosis (ALS) around half frontotemporal lobar degeneration (FTLD) 1,2 . A causal role for TDP-43 neurodegeneration is evidenced by dominantly inherited missense mutations TARDBP , the gene encoding TDP-43, that promote give rise to ALS FTLD 3–7 At least four types (A–D) with pathology (FTLD-TDP) are defined distinct brain distributions assembled associated different clinical presentations dementia 8 We previously showed, using cryo-electron microscopy, assembles into amyloid filaments type B FTLD-TDP 9 However, structures without remained unknown. Here we report microscopy from brains three individuals most common FTLD-TDP, A. formed a new fold was same across individuals, indicating this may characterize FTLD-TDP. resembles chevron badge unlike double-spiral-shaped establishing filament folds neurodegenerative conditions. structures, combination mass spectrometry, led identification two post-translational modifications citrullination monomethylation R293, indicate they facilitate formation observed structural variation individual filaments. will guide mechanistic studies assembly, as well development diagnostic therapeutic compounds proteinopathies.

Language: Английский

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Seeding the aggregation of TDP-43 requires post-fibrillization proteolytic cleavage

Nature Neuroscience, Journal Year: 2023, Volume and Issue: 26(6), P. 983 - 996

Published: May 29, 2023

Abstract Despite the strong evidence linking transactive response DNA-binding protein 43 (TDP-43) aggregation to pathogenesis of frontotemporal lobar degeneration with TDP-43, amyotrophic lateral sclerosis and several neurodegenerative diseases, our knowledge sequence structural determinants its neurotoxicity remains incomplete. Herein, we present a new method for producing recombinant full-length TDP-43 filaments that exhibit morphological features similar those brain-derived filaments. We show contain β-sheet-rich helical amyloid core is fully buried by flanking structured domains protein. demonstrate proteolytic cleavage exposure this are necessary propagating pathology enhancing seeding aggregates. Only exposed efficiently seeded endogenous in cells. These findings suggest inhibiting enzymes mediating aggregates represents viable disease-modifying strategy slow progression other proteinopathies.

Language: Английский

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Structural polymorphism of amyloid fibrils in ATTR amyloidosis revealed by cryo-electron microscopy

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 17, 2024

Abstract ATTR amyloidosis is caused by the deposition of transthyretin in form amyloid fibrils virtually every organ body, including heart. This systemic leads to a phenotypic variability that has not been molecularly explained yet. In brain conditions, previous studies suggest an association between clinical phenotype and molecular structures their fibrils. Here we investigate whether there such ATTRv patients carrying mutation I84S. Using cryo-electron microscopy, determined cardiac extracted from three ATTRv-I84S mutation, associated with consistent phenotype. We found each patient, exhibited different local conformations, these variations can co-exist within same fibril. Our finding suggests one disease may associate multiple fibril amyloidoses, calling for further studies.

Language: Английский

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TMEM106B core deposition associates with TDP-43 pathology and is increased in risk SNP carriers for frontotemporal dementia

Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(730)

Published: Jan. 17, 2024

Genetic variation at the transmembrane protein 106B gene ( TMEM106B) has been linked to risk of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) through an unknown mechanism. We found that presence TMEM106B rs3173615 protective genotype was associated longer survival after symptom onset in a postmortem FTLD-TDP cohort, suggesting slower disease course. The seminal discovery filaments derived from is common feature aging and, across range neurodegenerative disorders, suggests genetic variants could modulate and progression modulating aggregation. To explore this possibility assess pathological relevance accumulation, we generated new antibody targeting filament core sequence. Analysis samples revealed allele higher accumulation patients FTLD-TDP. In contrast, minimal deposition detected carriers allele. Although abundance monomeric full-length unchanged, exhibited increase dimeric TMEM106B. Increased also enhanced dysfunction, interactome data suggested role for impaired RNA transport, local translation, endolysosomal function Overall, these findings suggest prevention central mechanism by which haplotype reduces slows progression.

Language: Английский

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Human and mouse proteomics reveals the shared pathways in Alzheimer’s disease and delayed protein turnover in the amyloidome

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 11, 2025

Murine models of Alzheimer's disease (AD) are crucial for elucidating mechanisms but have limitations in fully representing AD molecular complexities. Here we present the comprehensive, age-dependent brain proteome and phosphoproteome across multiple mouse amyloidosis. We identified shared pathways by integrating with human metadata prioritized components multi-omics analysis. Collectively, two commonly used (5xFAD APP-KI) replicate 30% protein alterations; additional genetic incorporation tau splicing pathologies increases this similarity to 42%. dissected proteome-transcriptome inconsistency 5xFAD brains, revealing that inconsistent proteins enriched within amyloid plaque microenvironment (amyloidome). Our analysis turnover demonstrates formation delays degradation amyloidome components, including Aβ-binding autophagy/lysosomal proteins. proteomic strategy defines pathways, identifies potential targets, underscores contributes discrepancies during progression. This study maps changes models, identifying humans, amyloid-driven turnover, differences, offering insights into targets.

Language: Английский

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