Protein aggregation articles within Nature Communications

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  • Article
    | Open Access

    Interactions between α-synuclein fibrils and lipids have been associated with the development of Parkinson’s disease. This cryo-EM study reveals structural details of these interactions and suggests a mechanism for fibril-induced lipid extraction.

    • Benedikt Frieg
    • , Leif Antonschmidt
    •  & Gunnar F. Schröder

  • Article
    | Open Access

    This manuscript reports the structure of a pathologically relevant wild type ATTR amyloid fibril from systemic non-hereditary transthyretin amyloidosis. The comparison of the wild type ATTR fibril with two previous published ex vivo V30M ATTR fibrils highlighted numerous similarities between these different reconstructions, pointing to a common underlying structure for ATTR fibrils despite coming from different mutants and patients.

    • Maximilian Steinebrei
    • , Juliane Gottwald
    •  & Matthias Schmidt

  • Article
    | Open Access

    α-synuclein aggregates cause neuronal damage, but their heterogeneity complicates studying their toxic properties. Here, the authors analyze α-synuclein aggregates in vitro and study post-mortem brain samples, providing evidence that small aggregates are the main culprit for neuronal death in Parkinson’s disease.

    • Derya Emin
    • , Yu P. Zhang
    •  & David Klenerman

  • Article
    | Open Access

    Understanding how small molecules bind to pathological aggregates is of importance for therapeutic and diagnostic development in diseases such as Parkinson’s Disease. Here, the authors reveal a binding site of anle138b to lipid-induced α-synuclein fibrils.

    • Leif Antonschmidt
    • , Dirk Matthes
    •  & Loren B. Andreas

  • Article
    | Open Access

    The authors of this work characterize the effect of amino acid substitution on α-synuclein (α-Syn) aggregation. Residues 38 and 42 (in addition to 39) within the P1 region of α-Syn affect amyloid formation. The effect of substitution at position 38 is dependent on the amino-acid introduced, suggesting that specific interactions control α -Syn aggregation.

    • Sabine M. Ulamec
    • , Roberto Maya-Martinez
    •  & David J. Brockwell

  • Article
    | Open Access

    Ayala Mariscal et al have identified and characterized the interface of pathogenic Huntingtin and the molecular chaperone DNAJB1. Histidine-244 of the C-terminal domain of DNAJB1 is a key residues for binding to the poly-proline region of HTT. This binding site is specific for the interaction with Huntingtin.

    • S. M. Ayala Mariscal
    • , M. L. Pigazzini
    •  & J. Kirstein

  • Comment
    | Open Access

    The prion hypothesis embodies the radical concept that prion proteins contain the necessary information for infectious replication within their shape, thus obviating the requirement for genomic material. Two elegant papers by Hoyt et al. and Manka et al. describing high-resolution structures of infectious prions bring us closer to answering the long-standing question of how different prion conformations produce heritably distinct diseases.

    • Glenn C. Telling

  • Article
    | Open Access

    High-resolution structures of mammalian prions have remained elusive. Here, Manka et al. report the cryo-EM structure of infectious RML prion fibrils from mice. Structural similarity with recently reported infectious 263K prion fibrils from hamsters now suggests a common prion architecture.

    • Szymon W. Manka
    • , Wenjuan Zhang
    •  & Jonathan D. F. Wadsworth

  • Article
    | Open Access

    How ATP-independent chaperones release their clients without energy input remains enigmatic. Here the authors discover that chaperone Spy uses its long, disordered N terminus to facilitate client release through competitive, dynamic intramolecular interactions with Spy’s client binding surface.

    • Wei He
    • , Xinming Li
    •  & Shu Quan

  • Article
    | Open Access

    Interstitial Lung Disease (ILD)-associated mutations in surfactant protein C (SP-C) render the protein prone to aggregation. Here, the authors reveal their impact on protein maturation, provide insights into recognition of aggregation prone regions by chaperones, and address the autosomal dominant nature of ILD mutants.

    • Kristine F. R. Pobre-Piza
    • , Melissa J. Mann
    •  & Linda M. Hendershot

  • Article
    | Open Access

    The formyl peptide receptor 2 (FPR2) is involved in the pathogenesis of Alzheimer’s disease. Structures of FPR2 bound to Aβ42, humanin, or formyl peptides offer insight into Aβ42 neurotoxicity, humanin neuroprotection, and FPR ligand selectivity

    • Ya Zhu
    • , Xiaowen Lin
    •  & Beili Wu

  • Article
    | Open Access

    Generic approach for rapid prototyping is essential for the progress of synthetic biology. Here the authors modify the cell-free translation system to control protein aggregation and folding and validate the approach by using single conditions for prototyping of various disulfide-constrained polypeptides.

    • Yue Wu
    • , Zhenling Cui
    •  & Sergey Mureev

  • Article
    | Open Access

    Here, the authors present the cryo-EM structure of in vitro amyloid fibrils from recombinant SAA1.1 protein that were formed by seeding with fibrils purified from systemic AA amyloidosis tissue. This in vitro fibril structure resembles the structure of the ex vivo fibrils but differs from unseeded in vitro fibrils. These findings show that fibril morphologies can be propagated in vitro by seeding.

    • Thomas Heerde
    • , Matthies Rennegarbe
    •  & Marcus Fändrich

  • Article
    | Open Access

    Methods to quantitatively study liquid-liquid phase separation (LLPS) of proteins are lacking. Here the authors report Capillary flow experiments (Capflex) for the quantification of key LLPS parameters; they study Ddx4, the RP3 peptide and the aberrant liquid-to-solid phase transition of α-synuclein.

    • Emil G. P. Stender
    • , Soumik Ray
    •  & Alexander K. Buell

  • Article
    | Open Access

    The mechanisms underlying Huntingtin protein (Htt) aggregation are not fully understood. Here the authors perform a detailed investigation of the ultrastructural and biochemical properties of huntingtin cytoplasmic and nuclear inclusions, and reveal that they form via distinct mechanisms and exert their toxicity via different pathways.

    • Nathan Riguet
    • , Anne-Laure Mahul-Mellier
    •  & Hilal A. Lashuel

  • Article
    | Open Access

    AL amyloidosis is caused by the accumulation of overproduced light chain (LC) fragments as fibrils in patient organs and it is the most prevalent systemic amyloidosis. Here, the authors combine biochemical and biophysical experiments to characterise the lag phase of a patient-derived truncated LC and they identify structural transitions that precede fibril formation.

    • Pamina Kazman
    • , Ramona M. Absmeier
    •  & Johannes Buchner

  • Article
    | Open Access

    Alpha-1-antitrypsin (AAT) deficiency results from misfolding-prone AAT variants. Here the authors show that AAT forms co-translational folding intermediates on the ribosome that persist upon release and determine its folding fate. They show too that the ribosome can also modulate misfolding-prone AAT intermediates during their synthesis.

    • Elena Plessa
    • , Lien P. Chu
    •  & Lisa D. Cabrita

  • Article
    | Open Access

    Systemic AL amyloidosis is caused by misfolding of immunoglobulin light chains (LCs) but how post-translational modifications (PTMs) of LCs influence amyloid formation is not well understood. Here, the authors present the cryo-EM structure of an AL amyloid fibril derived from the heart tissue of a patient that is partially pyroglutamylated, N-glycosylated and contains an intramolecular disulfide bond. Based on their structure and biochemical experiments the authors conclude that the mutational changes, disulfide bond and glycosylation determine the fibril protein fold and that glycosylation protects the fibril core from proteolytic degradation.

    • Lynn Radamaker
    • , Sara Karimi-Farsijani
    •  & Marcus Fändrich

  • Article
    | Open Access

    Molecular chaperones from the Hsp70 family can break up protein aggregates, including amyloids. Here, the authors utilize microfluidic diffusional sizing to assess the mechanism of α-synuclein (αS) disaggregation by the Hsc70–DnaJB1–Apg2 system, and show that single αS molecules are removed directly from the fibril ends.

    • Matthias M. Schneider
    • , Saurabh Gautam
    •  & Tuomas P. J. Knowles

  • Article
    | Open Access

    Protein binding by the Hsp70/J-domain protein (JDP) chaperones prevents aggregation of the client protein. Here, the authors show that DnaJC7 binds preferentially to natively folded wild-type tau, via a β-turn element in tau that contains the known amyloid motif, while aggregation-prone tau mutants are recognized with reduced affinity.

    • Zhiqiang Hou
    • , Pawel M. Wydorski
    •  & Lukasz A. Joachimiak

  • Article
    | Open Access

    Aβ oligomers (AβO) are thought to represent the main toxic species in Alzheimer’s disease but very high Aβ concentrations are required to study them in vitro and it remains unknown what role these off-pathway oligomers play in vivo. Here, the authors use a dimeric variant of Aβ termed dimAβ, where two Aβ40 units are linked, which facilitates to study AβO formation kinetics and they observe that Aβ off-pathway oligomer formation is strongly accelerated at endo-lysosomal pH, while amyloid fibril formation is delayed. Furthermore, the authors demonstrate that dimAβ is a disease-relevant model construct for pathogenic AβO formation by showing that dimAβ AβOs target dendritic spines and induce AD-like somatodendritic Tau missorting.

    • Marie P. Schützmann
    • , Filip Hasecke
    •  & Wolfgang Hoyer

  • Article
    | Open Access

    Huntingtin exon-1 (HTTex1) consists of a N-terminal N17 domain, the disease causing polyQ domain and a C-terminal proline-rich domain (PRD). Here, the authors combine electron paramagnetic resonance (EPR), solid-state NMR with other biophysical method to characterise the structural differences of various HTTex1 fibril types with different toxicity and find that the dynamics and entanglement of the PRD domain differs among them and that the HTTex1 fibrils can be interconverted.

    • J. Mario Isas
    • , Nitin K. Pandey
    •  & Ansgar B. Siemer

  • Article
    | Open Access

    Amyloid aggregation of mutant p53 contributes to its loss of tumor suppressor function and oncogenic gain-of-function. Here, the authors use a protein mimetic to abrogate mutant p53 aggregation and rescue p53 function, which inhibits cancer cell proliferation in vitro and halts tumor growth in vivo.

    • L. Palanikumar
    • , Laura Karpauskaite
    •  & Mazin Magzoub

  • Article
    | Open Access

    α-Synuclein (αS) aggregation is a driver of several neurodegenerative disorders. Here, the authors identify a class of peptides that bind toxic αS oligomers and amyloid fibrils but not monomeric functional protein, and prevent further αS aggregation and associated cell damage.

    • Jaime Santos
    • , Pablo Gracia
    •  & Salvador Ventura

  • Article
    | Open Access

    Wobble uridine (U34) tRNA modifications are important for the decoding of AA-ending codons. Here the authors show that while the U34-codon content of mRNAs are predictive of changes in ribosome translation elongation, the resulting outcome in protein expression also relies on specific hydrophilic motifs-dependent protein aggregation and clearance.

    • Francesca Rapino
    • , Zhaoli Zhou
    •  & Pierre Close

  • Article
    | Open Access

    The self-assembly of α-synuclein (αS) is a pathological feature of Parkinson’s disease. The αS species responsible for neuronal damage are not well characterized. Here, the authors show that αS fibrils release soluble prefibrillar oligomeric species responsible for neurotoxicity in vitro.

    • Roberta Cascella
    • , Serene W. Chen
    •  & Cristina Cecchi

  • Article
    | Open Access

    Systemic AA amyloidosis is a protein misfolding disease caused by the formation of amyloid fibrils from serum amyloid A (SAA) protein. Here, the authors present the cryo-EM structures of AA amyloid fibrils isolated from mouse tissue and in vitro formed fibrils, which differ in their structures and they also show that the ex vivo fibrils are more resistant to proteolysis than the in vitro fibrils and propose that pathogenic amyloid fibrils might originate from proteolytic selection.

    • Akanksha Bansal
    • , Matthias Schmidt
    •  & Marcus Fändrich

  • Article
    | Open Access

    Systemic AL amyloidosis is a protein misfolding disease caused by the aggregation and fibrillation of immunoglobulin light chains (LCs). Here, the authors present the cryo-EM structures of λ3 LC-derived amyloid fibrils that were isolated from patient tissue and they observe structural breaks, where the two different fibril structures co-exist at different z-axial positions within the same fibril.

    • Lynn Radamaker
    • , Julian Baur
    •  & Marcus Fändrich

  • Article
    | Open Access

    Our understanding of the molecular mechanisms underlying pathological protein aggregation remains incomplete. Here, single molecule infrared nanospectroscopy (AFM-IR) offers insight into the structure of Aβ42 oligomeric and fibrillar species and their interaction with an aggregation inhibitor, paving the way for single molecule drug discovery studies.

    • Francesco Simone Ruggeri
    • , Johnny Habchi
    •  & Tuomas P. J. Knowles

  • Article
    | Open Access

    α1-Antitrypsin (AAT) is a 52 kDa serum glycoprotein, the misfolding and polymerisation of which is associated with COPD and liver disease. Here the authors demonstrate the use of high-resolution multidimensional solution-state NMR spectroscopy to characterise the structure and dynamics in solution of Z AAT purified directly from clinical patients.

    • Alistair M. Jagger
    • , Christopher A. Waudby
    •  & David A. Lomas

  • Article
    | Open Access

    Identifying factors that enable cells to induce a potent stress response to amyloid-like aggregation can provide further insight into the mechanism of stress regulation. Here, the authors express polyglutamine-expanded Huntingtin as a model disease protein in yeast cells and perform a genetic screen for chaperone factors that allow yeast cells to activate a potent stress response. They identify Sis1, an essential Hsp40 co-chaperone of Hsp70, as a critical sensor of proteotoxic stress and further show that both Sis1 and its mammalian homolog DnaJB6 regulate the magnitude of the cellular heat stress response, indicating that this mechanism is conserved.

    • Courtney L. Klaips
    • , Michael H. M. Gropp
    •  & F. Ulrich Hartl

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