Protein folding articles within Nature Communications

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• Article
  10 August 2022 | Open Access

  Identification of a HTT-specific binding motif in DNAJB1 essential for suppression and disaggregation of HTT

  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

• Article
  06 August 2022 | Open Access

  Molecular mechanism for the synchronized electrostatic coacervation and co-aggregation of alpha-synuclein and tau

  Here, the authors report that α-synuclein phase-separates into liquid condensates with positively charged polypeptides such as Tau. The condensates undergo different maturation processes, including the formation of α-synuclein/Tau amyloid hetero-aggregates inside the condensates.

  • Pablo Gracia
  • , David Polanco
  •  & Nunilo Cremades

• Article
  05 August 2022 | Open Access

  Disease-associated mutations within the yeast DNAJB6 homolog Sis1 slow conformer-specific substrate processing and can be corrected by the modulation of nucleotide exchange factors

  Here the authors describe mechanisms through which analogous LGMDD1 (Limb-Girdle Muscular Dystrophy Type D1) mutations affect Sis1 (a yeast functional homolog of human DNAJB6) chaperone activity and poison the function of wild-type protein; potentially uncovering a new therapeutic route to explore.

  • Ankan K. Bhadra
  • , Michael J. Rau
  •  & Heather L. True

• Article
  27 July 2022 | Open Access

  The Cryo-EM structures of two amphibian antimicrobial cross-β amyloid fibrils

  In this work the authors provide high-resolution structural support for the amyloid-antimicrobial link via functional amyloids displaying propeller-like and kinked cross-β fibrils.

  • Robert Bücker
  • , Carolin Seuring
  •  & Meytal Landau

• Article
  22 July 2022 | Open Access

  Heparin induces α-synuclein to form new fibril polymorphs with attenuated neuropathology

  The Cryo-EM structures reported in this work reveal how heparin incorporates into α-syn fibril formation to determine fibril polymorphs. This highlights the role of biological polymers in the conformational selection and neuropathological regulation of amyloid fibrils.

  • Youqi Tao
  • , Yunpeng Sun
  •  & Dan Li

• Article
  22 July 2022 | Open Access

  Modulating co-translational protein folding by rational design and ribosome engineering

  The narrow exit tunnel of the ribosome is important for cotranslational protein folding. Here, authors show that their rationally designed and engineered exit tunnel protein loops modulate the free energy of nascent chain dynamics and folding.

  • Minkoo Ahn
  • , Tomasz Włodarski
  •  & John Christodoulou

• Article
  15 July 2022 | Open Access

  Trigger factor both holds and folds its client proteins

  Using Guanidium HCl denatured glyceraldehyde 3-phosphate dehydrogenase (GAPDH), the authors provide in vitro evidence for the active involvement of the trigger factor (TF) in promoting the native folding of pre-unfolded client proteins, by preventing non-productive self-associations (misfolding) and by shielding oligomeric interfaces from aggregation.

  • Kevin Wu
  • , Thomas C. Minshull
  •  & James C. A. Bardwell

• Comment
  13 July 2022 | Open Access

  The shape of things to come: structural insights into how prion proteins encipher heritable information

  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
  13 July 2022 | Open Access

  2.7 Å cryo-EM structure of ex vivo RML prion fibrils

  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
  01 July 2022 | Open Access

  Many dissimilar NusG protein domains switch between α-helix and β-sheet folds

  Folded proteins are composed of secondary structures, α-helices and β-sheets, that are generally assumed to be stable. Here, the authors combine computational prediction with experimental validation to show that many sequence-diverse NusG protein domains switch completely from α-helix to β-sheet folds.

  • Lauren L. Porter
  • , Allen K. Kim
  •  & Marie-Paule Strub

• Article
  27 June 2022 | Open Access

  Structural basis for defective membrane targeting of mutant enzyme in human VLCAD deficiency

  Prew et al. uncovered a structural basis for human VLCAD deficiency that arises from point mutations within the enzyme’s membrane-binding region, which was shown to fold as a putative α-helical hairpin. Helix-breaking mutations selectively disrupt membrane interaction and thus homeostatic function.

  • Michelle S. Prew
  • , Christina M. Camara
  •  & Loren D. Walensky

• Article
  24 June 2022 | Open Access

  Coordination of metal center biogenesis in human cytochrome c oxidase

  Mitochondrial cytochrome c oxidase is a heme aa3-copper oxygen reductase. Here, authors report that metal center-specific metallochaperones form dynamic assemblies to control heme a biosynthesis and coordinate copper transfer to the copper sites.

  • Eva Nývltová
  • , Jonathan V. Dietz
  •  & Antoni Barrientos

• Article
  17 June 2022 | Open Access

  Cryo-EM structure of an amyloid fibril formed by full-length human SOD1 reveals its conformational conversion

  Misfolded SOD1 has been linked to both familial and sporadic ALS. Here the authors have determined the cryo-EM structure of SOD1 fibrils, providing insights into the conversion of SOD1 from its immature form into an aggregated form during pathogenesis of ALS.

  • Li-Qiang Wang
  • , Yeyang Ma
  •  & Yi Liang

• Article
  14 June 2022 | Open Access

  Structural remodeling of ribosome associated Hsp40-Hsp70 chaperones during co-translational folding

  Ribosome associated complex (RAC)- HSP70 (Ssb in yeast) is a eukaryotic chaperone system involved in co-translational folding. Here, authors report structures of RAC-containing ribosomal complexes, which suggest a working model for the dynamic actions of RAC-Ssb during the process.

  • Yan Chen
  • , Bin Tsai
  •  & Ning Gao

• Article
  13 June 2022 | Open Access

  Neurotoxic amyloidogenic peptides in the proteome of SARS-COV2: potential implications for neurological symptoms in COVID-19

  Here the authors report the formation of toxic clumps of protein, similar to amyloid assemblies found in Alzheimer’s disease and suggest their possible role for some of the neurological symptoms of long-COVID.

  • Mirren Charnley
  • , Saba Islam
  •  & Nicholas P. Reynolds

• Article
  02 June 2022 | Open Access

  Universal protein misfolding intermediates can bypass the proteostasis network and remain soluble and less functional

  Nissley and co-workers predict protein misfolding into kinetically trapped, entangled conformations that can bypass the proteostasis network to remain soluble but less-functional for long timescales is widespread within the E. coli proteome.

  • Daniel A. Nissley
  • , Yang Jiang
  •  & Edward P. O’Brien

• Article
  27 May 2022 | Open Access

  Fluent molecular mixing of Tau isoforms in Alzheimer’s disease neurofibrillary tangles

  The tau protein in Alzheimer’s disease contains two isoforms. Using solid-state NMR and seeded growth of isotopically labeled tau, here the authors determined that the two isoforms mix fluently on the molecular level to propagate the AD tau structure.

  • Aurelio J. Dregni
  • , Pu Duan
  •  & Mei Hong

• Article
  27 May 2022 | Open Access

  Improving recombinant protein production by yeast through genome-scale modeling using proteome constraints

  Due to the complexity of the protein secretory pathway, strategy suitable for the production of a certain recombination protein cannot be generalized. Here, the authors construct a proteome-constrained genome-scale protein secretory model for yeast and show its application in the production of different misfolded or recombinant proteins.

  • Feiran Li
  • , Yu Chen
  •  & Jens Nielsen

• Article
  20 May 2022 | Open Access

  Insights into the client protein release mechanism of the ATP-independent chaperone Spy

  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
  20 May 2022 | Open Access

  Codon-specific Ramachandran plots show amino acid backbone conformation depends on identity of the translated codon

  Genetic code redundancies are considered inconsequential to protein structure. This study uncovers a dependence between local amino acid conformation in folded proteins and the identity of the codon from which that amino acid was translated.

  • Aviv A. Rosenberg
  • , Ailie Marx
  •  & Alex M. Bronstein

• Article
  19 May 2022 | Open Access

  Templated folding of the RTX domain of the bacterial toxin adenylate cyclase revealed by single molecule force spectroscopy

  The authors use optical tweezers to show that the folding of repeats-in-toxin (RTX) block-iv in adenylate cyclase is templated by the folded RTX block-v. The findings suggest a possible mechanism for transmitting the folding signal in the RTX domain.

  • Han Wang
  • , Guojun Chen
  •  & Hongbin Li

• Article
  16 May 2022 | Open Access

  Ca²⁺-mediated higher-order assembly of heterodimers in amino acid transport system b^0,+ biogenesis and cystinuria

  Cystinuria is caused by mutations in heterodimeric amino acid transporter known as system b^0,+. Here, authors discover that Ca²⁺ stabilizes the interface between two system b^0,+ regulatory subunits rBAT, leading to super-dimerization of the b^0,+AT–rBAT heterodimer, facilitating system b^0,+ maturation.

  • Yongchan Lee
  • , Pattama Wiriyasermkul
  •  & Shushi Nagamori

• Article
  16 May 2022 | Open Access

  Hyperphosphorylated tau self-assembles into amorphous aggregates eliciting TLR4-dependent responses

  In this work, the authors report that hyperphosphorylated recombinant tau spontaneously assembles into small, amorphous aggregates, which disrupt membranes and induce Toll-like receptor 4-dependent responses in human macrophages.

  • Jonathan X. Meng
  • , Yu Zhang
  •  & David Klenerman

• Article
  06 May 2022 | Open Access

  Stress-induced protein disaggregation in the endoplasmic reticulum catalysed by BiP

  Aggregation of misfolded proteins underlie dementias. Here, the authors show that stressed cells activate an innate mechanism to resolve aggregates of defective proteins in the endoplasmic reticulum, where a third of cellular proteins are produced.

  • Eduardo Pinho Melo
  • , Tasuku Konno
  •  & Edward Avezov

• Article
  27 April 2022 | Open Access

  Three-dimensional structure determination of protein complexes using matrix-landing mass spectrometry

  Mass spectrometry (MS) is a powerful tool for the structural characterization of protein complexes. Here the authors offer a path for direct integration of MS and electron microscopy with a MS approach that enables grid deposition and structural preservation of gaseous protein complex ions.

  • Michael S. Westphall
  • , Kenneth W. Lee
  •  & Joshua J. Coon

• Article
  14 April 2022 | Open Access

  Hidden information on protein function in censuses of proteome foldedness

  Proteomics can define features of proteome foldedness by assessing the reactivity of surface exposed amino acids. Here, the authors show that such exposure patterns yield insight to structural changes in chaperones as they bind to unfolded proteins in urea-denatured mammalian cell lysate.

  • Dezerae Cox
  • , Ching-Seng Ang
  •  & Danny M. Hatters

• Article
  05 April 2022 | Open Access

  Mapping SP-C co-chaperone binding sites reveals molecular consequences of disease-causing mutations on protein maturation

  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
  01 April 2022 | Open Access

  Structural basis of FPR2 in recognition of Aβ₄₂ and neuroprotection by humanin

  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
  30 March 2022 | Open Access

  Cyclophilin anaCyp40 regulates photosystem assembly and phycobilisome association in a cyanobacterium

  Cyclophilins are proteins found in many organisms, where they can play roles as chaperones, in signal transduction, or other functions. Here, Yadav et al. show that a cyanobacterial cyclophilin is involved in stress responses and in assembly of photosynthetic complexes, and displays unique structural features.

  • Shivam Yadav
  • , Martin Centola
  •  & Enrico Schleiff

• Article
  18 March 2022 | Open Access

  Characterization of protein unfolding by fast cross-linking mass spectrometry using di-ortho-phthalaldehyde cross-linkers

  Conformations sampled by a protein while it unfolds are difficult to visualize. Here, the authors develop di-ortho-phthalaldehyde cross-linkers for rapid chemical cross-linking mass spectrometry analysis and demonstrate that this method captures the conformations of protein unfolding intermediates.

  • Jian-Hua Wang
  • , Yu-Liang Tang
  •  & Xiaoguang Lei

• Article
  15 March 2022 | Open Access

  Mapping the sequence specificity of heterotypic amyloid interactions enables the identification of aggregation modifiers

  In this work, Louros et al. uncover a rule book for interactions of amyloids with other proteins. This grammar was shown to promote cellular spreading of tau aggregates in cells, but can also be harvested to develop structure-based aggregation blockers.

  • Nikolaos Louros
  • , Meine Ramakers
  •  & Joost Schymkowitz

• Article
  03 March 2022 | Open Access

  Spatiotemporal modulations in heterotypic condensates of prion and α-synuclein control phase transitions and amyloid conversion

  The authors show that prion protein and α-synuclein undergo phase separation through domain-specific electrostatic interactions. These complex coacervates possess electrostatic nanoclusters and can convert into multiphasic condensates and amyloids.

  • Aishwarya Agarwal
  • , Lisha Arora
  •  & Samrat Mukhopadhyay

• Article
  26 January 2022 | Open Access

  Differential roles for DNAJ isoforms in HTT-polyQ and FUS aggregation modulation revealed by chaperone screens

  Here, using quantitative screens in human cells, the authors reveal distinct effects of naturally-occurring DNAJ chaperone isoforms on pathological aggregation of the Huntington’s disease-associated HTT-polyQ and the ALS-related mutant FUS.

  • Kinneret Rozales
  • , Amal Younis
  •  & Reut Shalgi

• Article
  11 January 2022 | Open Access

  Towards a generic prototyping approach for therapeutically-relevant peptides and proteins in a cell-free translation system

  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
  10 January 2022 | Open Access

  Cryo-EM demonstrates the in vitro proliferation of an ex vivo amyloid fibril morphology by seeding

  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
  15 December 2021 | Open Access

  Decoding non-canonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1α

  IRE1 helps mitigate endoplasmic-reticulum stress by cleaving specific mRNAs at a conserved sequence endomotif via regulated IRE1-dependent decay (RIDD). Here the authors discover a more promiscuous IRE1 activity dubbed RIDD lacking endomotif (RIDDLE).

  • Adrien Le Thomas
  • , Elena Ferri
  •  & Avi Ashkenazi

• Article
  15 December 2021 | Open Access

  Capillary flow experiments for thermodynamic and kinetic characterization of protein liquid-liquid phase separation

  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
  08 December 2021 | Open Access

  Plasticity within the barrel domain of BamA mediates a hybrid-barrel mechanism by BAM

  The β-barrel assembly machinery (BAM) assists the folding and membrane insertion of bacterial outer membrane proteins. Here, the authors report structural characterization of BAM in lipid environment and in complex with the client protein EspP integrated into the barrel of BamA, providing insight into BAM mechanism of function.

  • Runrun Wu
  • , Jeremy W. Bakelar
  •  & Nicholas Noinaj

• Article
  07 December 2021 | Open Access

  Plasmin activity promotes amyloid deposition in a transgenic model of human transthyretin amyloidosis

  ATTR amyloidosis causes heart failure through the accumulation of misfolded transthyretin in cardiac muscle. Here the authors report a mouse model of ATTR amyloidosis and demonstrate the involvement of protease activity in ATTR amyloid deposition.

  • Ivana Slamova
  • , Rozita Adib
  •  & J. Paul Simons

• Article
  06 December 2021 | Open Access

  Monitoring the binding and insertion of a single transmembrane protein by an insertase

  The insertion and folding nascent or fully synthesized polypeptides into membranes is assisted by insertases. Here, the authors use a range of biophysical approaches to provide molecular details of how the transmembrane insertase YidC facilitates the insertion a protein into a phospholipid membrane.

  • Pawel R. Laskowski
  • , Kristyna Pluhackova
  •  & Daniel J. Müller

• Article
  29 November 2021 | Open Access

  Two-colour single-molecule photoinduced electron transfer fluorescence imaging microscopy of chaperone dynamics

  Revealing mechanisms of complex protein machines requires simultaneous exploration of multiple structural coordinates. Here the authors report two-colour fluorescence microscopy combined with photoinduced electron transfer probes to simultaneously detect two structural coordinates in single protein molecules.

  • Jonathan Schubert
  • , Andrea Schulze
  •  & Hannes Neuweiler

• Article
  25 November 2021 | Open Access

  Plant LHC-like proteins show robust folding and static non-photochemical quenching

  Plant light harvesting complex (LHC)‐like proteins protect the photosynthetic machinery from excess light. Here the authors show that plant LHC‐like dimers are stabilized by associated pigments and can quench chlorophyll fluorescence via direct energy transfer from chlorophyll to zeaxanthin.

  • Petra Skotnicová
  • , Hristina Staleva-Musto
  •  & Roman Sobotka

• Article
  18 November 2021 | Open Access

  Phosphorylation activates the yeast small heat shock protein Hsp26 by weakening domain contacts in the oligomer ensemble

  Small heat shock proteins (sHsps) form large spherical assemblies and their regulation is not well understood. Here, the authors provide insights into the mechanism of Hsp26 activation by characterising phospho-mimetic mutants of yeast Hsp26. They present cryo-EM structures of the wild-type Hsp26 40mer and its phospho-mimetic mutants that reveal the location of the thermosensor in the oligomer, and the authors also show that the thermosensor domain is targeted by phosphorylation, which relieves the intrinsic inhibition of chaperone activity.

  • Moritz Mühlhofer
  • , Carsten Peters
  •  & Johannes Buchner

• Article
  12 November 2021 | Open Access

  Nuclear and cytoplasmic huntingtin inclusions exhibit distinct biochemical composition, interactome and ultrastructural properties

  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
  11 November 2021 | Open Access

  Dissection of the amyloid formation pathway in AL amyloidosis

  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
  08 November 2021 | Open Access

  Nascent chains can form co-translational folding intermediates that promote post-translational folding outcomes in a disease-causing protein

  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
  05 November 2021 | Open Access

  Role of mutations and post-translational modifications in systemic AL amyloidosis studied by cryo-EM

  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
  01 November 2021 | Open Access

  Dynamic interactions and Ca²⁺-binding modulate the holdase-type chaperone activity of S100B preventing tau aggregation and seeding

  The calcium binding protein S100B is an abundantly expressed protein in the brain and has neuro-protective functions by inhibiting Aβ aggregation and metal ion toxicity. Here, the authors combine cell biology and biochemical experiments with chemical kinetics and NMR measurements and show that S100B protein is an extracellular Tau chaperone and further characterize the interactions between S100B and Tau.

  • Guilherme G. Moreira
  • , François-Xavier Cantrelle
  •  & Cláudio M. Gomes

• Article
  19 October 2021 | Open Access

  A dual-reporter system for investigating and optimizing protein translation and folding in E. coli

  Heterologous expression of recombinant proteins often results in misfolding, aggregation and degradation. Here, we show an in vivo dual-biosensor system that simultaneously assesses protein translation and protein folding, thereby enabling rapid screening of expression strains as well as mutant libraries.

  • Ariane Zutz
  • , Louise Hamborg
  •  & Alex Toftgaard Nielsen

• Article
  14 October 2021 | Open Access

  The Hsc70 disaggregation machinery removes monomer units directly from α-synuclein fibril ends

  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