Protein folding

  • Article
    | Open Access

    Aggregation is sequence-specific and nucleated by short aggregating protein segments (APR). Here authors use a multidisciplinary approach to show that in E.coli some frequently occurring APRs lead to protein aggregation and ultimately bacterial cell death, which could serve as antibacterial strategy.

    • Ladan Khodaparast
    • , Laleh Khodaparast
    •  & Joost Schymkowitz
  • Article
    | Open Access

    Amyloid fibril structures can display polymorphism. Here the authors reveal the cryo-EM structures of several different fibril morphologies of a peptide derived from an amyloidogenic immunoglobulin light chain and present a mathematical analysis of physical factors that influence fibril polymorphism.

    • William Close
    • , Matthias Neumann
    •  & Marcus Fändrich
  • Article
    | Open Access

    The U-box ubiquitin ligase UFD-2 is one of the most abundant components of the ubiquitin proteasome system in muscle cells. Here the authors perform in vitro and in vivo experiments and show that UFD-2 has E3 ligase activity and that it ubiquitinates unfolded myosin using the C. elegans myosin chaperone UNC-45 as an adaptor protein.

    • Doris Hellerschmied
    • , Max Roessler
    •  & Tim Clausen
  • Article
    | Open Access

    A pool of quality control proteins (QC) maintains the protein-folding homeostasis in the cell, but its quantitative analysis is challenging. Here the authors develop a FRET sensor based on the protein barnase, able to quantify QC holdase activity and its ability to suppress protein aggregation.

    • Rebecca J. Wood
    • , Angelique R. Ormsby
    •  & Danny M. Hatters
  • Article
    | Open Access

    The Hsp90 chaperone cycle is influenced by multiple phosphorylation events but their regulatory functions are poorly understood. Here, the authors show that phosphorylation and unfolding of cochaperone Cdc37 tailors the Hsp90 chaperone cycle by recruiting kinases that promote distinct phosphorylation patterns.

    • Ashleigh B. Bachman
    • , Dimitra Keramisanou
    •  & Ioannis Gelis
  • Article
    | Open Access

    Protein phosphatase 2A (PP2A) forms different holoenzymes but little is known about the disassembly of these important signalling complexes. Here the authors present the crystal structure of PP2A bound to TOR signaling pathway regulator (TIPRL) and give insights into the methylation-dependent disassembly of PP2A holenzymes.

    • Cheng-Guo Wu
    • , Aiping Zheng
    •  & Yongna Xing
  • Article
    | Open Access

    Porins, like OmpG, are embedded in the outer membrane of bacteria and facilitate uptake and secretion of nutrients and ions. Here the authors present a protocol for solid state NMR structure determination of proteins larger than 25 kDa and use it to structurally characterize membrane embedded OmpG.

    • Joren S. Retel
    • , Andrew J. Nieuwkoop
    •  & Hartmut Oschkinat
  • Article
    | Open Access

    The BRICHOS domain is a chaperone that can act against amyloid-β peptide fibril formation and non-fibrillar protein aggregation. Here the authors use a multidisciplinary approach and show that the Bri2 BRICHOS domain has qualitatively different chaperone activities depending on its quaternary structure.

    • Gefei Chen
    • , Axel Abelein
    •  & Jan Johansson
  • Article
    | Open Access

    The bacterial chaperone Trigger Factor (TF) is a dynamic protein and its dimer structure is unknown. Here the authors present a protocol combining NMR, computational and biophysical methods for the structural characterization of large dynamic protein complexes and show that TF forms a symmetric head-to-tail dimer.

    • Leonor Morgado
    • , Björn M. Burmann
    •  & Sebastian Hiller
  • Article
    | Open Access

    Misfolding of superoxide dismutase 1 (SOD1) is linked to amyotrophic lateral sclerosis. Here the authors characterize the unfolding/refolding of single SOD1 molecules using optical tweezers, identifying partially folded intermediates that lead to misfolding after the formation of a native-like core.

    • Supratik Sen Mojumdar
    • , Zackary N. Scholl
    •  & Michael T. Woodside
  • Article
    | Open Access

    Changes in chromatin structure have been linked to organismal ageing. Here the authors show that altered histone expression and mitochondrial stress during C. elegans development result in chromatin changes and a cytosolic stress response that affects organismal longevity, and depends on HSF-1 and the chromatin remodeller, ISW-1.

    • Olli Matilainen
    • , Maroun S. Bou Sleiman
    •  & Johan Auwerx
  • Article
    | Open Access

    The Alzheimer protein Tau interacts with biological membranes, but the role of these interactions in regulating Tau function in health and disease remains unexplored. Here, the authors report on the discovery and characterization of neurotoxic oligomeric protein/phospholipid complexes.

    • Nadine Ait-Bouziad
    • , Guohua Lv
    •  & Hilal A. Lashuel
  • Article
    | Open Access

    The effect of knots on protein stability and folding kinetics is not well understood. Here the authors combine optical tweezer experiments and calculations to experimentally determine the energy cost for knot formation, which indicates that knotted proteins evolved specific folding pathways because knot formation in unfolded chains is unfavorable.

    • Andrés Bustamante
    • , Juan Sotelo-Campos
    •  & Mauricio Báez
  • Article
    | Open Access

    Improving recombinant protein expression and stabilization remains a significant challenge. Here, the authors engineer Archaeoglobus fulgidus ferritin as a thermostable exoshell to provide steric accommodation and charge complementation for recombinant proteins, which can improve yields by 100 fold.

    • Siddharth Deshpande
    • , Nihar D. Masurkar
    •  & Chester L. Drum
  • Article
    | Open Access

    Aggregation of amyloidogenic peptides into fibrils and crystals has incidence in several amyloid-related diseases. Here, the authors investigate the origins of the fibril-to-crystal conversion in amyloidogenic hexapeptides pointing to the amyloid crystals as the ground state in the protein folding energy landscape.

    • Nicholas P. Reynolds
    • , Jozef Adamcik
    •  & Raffaele Mezzenga
  • Article
    | Open Access

    The Bam complex promotes the insertion of β-barrel proteins (such as UpaG, a trimeric autotransporter adhesin) into the bacterial outer membrane. Here, Sikdar et al. show that UpaG β-barrel segments fold into a trimeric structure in the periplasm before they interact with the Bam complex.

    • Rakesh Sikdar
    • , Janine H. Peterson
    •  & Harris D. Bernstein
  • Article
    | Open Access

    It is hypothesised that exposure to bovine spongiform encephalopathy through contaminated food could have resulted in a large proportion of latent variant Creutzfeldt-Jakob disease cases in humans. Here the authors demonstrate that inoculation with blood from non-symptomatic, vCJD infected humans, results in a unique prion-like disorder in mice and macaques.

    • Emmanuel E. Comoy
    • , Jacqueline Mikol
    •  & Jean-Philippe Deslys
  • Article
    | Open Access

    Hsp70s are highly conserved molecular chaperones that play multiple essential roles in maintaining cellular protein homeostasis. Here, the authors provide structural evidence for active substrate release by Hsp70s upon ATP binding and provide insight into the molecular mechanism of ATP-driven Hsp70 chaperone activity.

    • Jiao Yang
    • , Yinong Zong
    •  & Qinglian Liu
  • Article
    | Open Access

    The yeast Hsp70 homolog Ssb is a chaperone that binds translating ribosomes where it is thought to function primarily by promoting nascent peptide folding. Here the authors find that the ribosome biogenesis defect associated with the loss of Ssb is attributable to a specific disruption in TORC1 signaling rather than defects in ribosomal protein folding.

    • Kaivalya Mudholkar
    • , Edith Fitzke
    •  & Sabine Rospert
  • Article
    | Open Access

    Prion diseases can be transmitted across species. Here the authors use solid-state NMR to study prion protein (PrP) amyloids from human, mouse and Syrian hamster and show that their structural differences are mainly governed by two residues, which helps to understand interspecies PrP propagation on a molecular level.

    • Theint Theint
    • , Philippe S. Nadaud
    •  & Christopher P. Jaroniec
  • Article
    | Open Access

    Proteins fold under mechanical force during co-translational folding at the ribosome. Here, the authors use single molecule magnetic tweezers to study the influence of chaperones on protein folding and show that the ribosomal chaperone trigger factor acts as a mechanical foldase by promoting protein folding under force.

    • Shubhasis Haldar
    • , Rafael Tapia-Rojo
    •  & Julio M. Fernandez
  • Article
    | Open Access

    Seeding of amyloid beta from one brain region to another is thought to contribute to the progression of Alzheimer’s disease, although to date most studies have depended on inoculation of animals with exogenous amyloid. Here the authors describe a genetic seed and target system in Drosophila which may be useful for the mechanistic study of seeding of amyloid in vivo.

    • Ramona F. Sowade
    •  & Thomas R. Jahn
  • Article
    | Open Access

    Proteostasis is maintained through a number of molecular mechanisms, some of which function to protect the folded state of proteins. Here the authors demonstrate the use of TPE-MI in a fluorigenic dye assay for the quantitation of unfolded proteins that can be used to assess proteostasis on a cellular or proteome scale.

    • Moore Z. Chen
    • , Nagaraj S. Moily
    •  & Danny M. Hatters
  • Article
    | Open Access

    The F508 deletion (F508del) in the cystic fibrosis transmembrane conductance regulator (CFTR) is the most common CF causing mutation. Here the authors show that cytosolic chaperones shift the F508del channel conformation to the native fold by kinetic and thermodynamic remodelling of the gating energetics towards that of wild-type CTFR.

    • Miklos Bagdany
    • , Guido Veit
    •  & Gergely L. Lukacs
  • Article
    | Open Access

    TDP-43 aggregation is linked to various diseases including amyotrophic lateral sclerosis. Here the authors show that acetylation of the protein triggers TDP-43 pathology in cultured cells and mouse skeletal muscle, which can be cleared through an HSF1-dependent chaperone mechanism that disaggregates the protein.

    • Ping Wang
    • , Connor M. Wander
    •  & Todd J. Cohen
  • Article
    | Open Access

    In the prevailing model for assisted protein folding, chaperonins act passively by preventing protein aggregation. Here, the authors use single-molecule fluorescence measurements and cryo-electron microscopy and show that theE. coliGroELS chaperonin system also has an active role in folding the endogenous bacterial protein PepQ.

    • Jeremy Weaver
    • , Mengqiu Jiang
    •  & Hays S. Rye
  • Article
    | Open Access

    IRE1α is an ER stress sensor, whose activity induces apoptosis. Here, the authors report that fortilin, a pro-survival factor, with yet unknown roles in ER stress, interacts with active IRE1α, inhibits both its kinase end RNase activities, and protects cells from apoptosis both in vitro and in vivo.

    • Decha Pinkaew
    • , Abhijnan Chattopadhyay
    •  & Ken Fujise
  • Article
    | Open Access

    The eukaryotic heat shock protein 90 (Hsp90) undergoes an ATP-dependent conformational cycle that is influenced by posttranslational modifications and co-chaperones. Here, the authors show that the yeast co-chaperone Hch1 can be functionally substituted by site-specific phosphorylation in human Hsp90.

    • Abbey D. Zuehlke
    • , Michael Reidy
    •  & Len Neckers
  • Article
    | Open Access

    The properties of many transmembrane or aggregation-prone proteins make them difficult to recombinantly express. Here the authors use a modified N-terminal domain of a spider silk protein to express and purify several difficult to express proteins at levels considerably higher than with conventional tags.

    • Nina Kronqvist
    • , Médoune Sarr
    •  & Jan Johansson
  • Article
    | Open Access

    Studying the physiological confirmation of amyloid β (Aβ) and amyloid precursor protein (APP) often uses techniques that could disrupt their conformation. Here, the authors use non-destructive microscopy approaches to study the confirmation of Aβ and APP in mouse models of Alzheimer’s disease.

    • O. Klementieva
    • , K. Willén
    •  & G. K. Gouras
  • Article
    | Open Access

    The TIM barrel fold is an evolutionarily conserved motif found in proteins with a variety of enzymatic functions. Here the authors explore the fitness landscape of the TIM barrel protein IGPS and uncover evolutionary constraints on both sequence and structure, accompanied by long range allosteric interactions.

    • Yvonne H. Chan
    • , Sergey V. Venev
    •  & C. Robert Matthews
  • Article
    | Open Access

    The translocon-associated protein complex (TRAP) is a crucial component of the endoplasmic reticulum protein translocon. Here the authors study native translocon structures from human disease patients and algae cells to determine the molecular organization of the TRAP complex.

    • Stefan Pfeffer
    • , Johanna Dudek
    •  & Friedrich Förster
  • Article
    | Open Access

    Mild heat stress has beneficial effects on organismal health and survival. Here, Kumstaet al. show that a mild heat shock and HSF-1 overexpression induce autophagy in multiple tissues of C. elegansand autophagy-related genes are essential for both heat shock-induced and HSF-1–mediated stress resistance and longevity.

    • Caroline Kumsta
    • , Jessica T. Chang
    •  & Malene Hansen
  • Article
    | Open Access

    Huntington’s disease (HD) is caused by misfolding of mutant Htt protein. The authors find that in HD models, the decreased expression of heat shock transcription factor 1 that usually protects against protein misfolding, is in part caused by elevated CK2α’ kinase and Fbxw7 E3 ligase expression.

    • Rocio Gomez-Pastor
    • , Eileen T. Burchfiel
    •  & Dennis J. Thiele
  • Article
    | Open Access

    The correct folding of proteins often requires the intervention molecular chaperones, which can occur co-translationally. Here the authors identify elements of yeast Ssb (Hsp70) that mediate ribosomal binding, and suggest a mechanism that directs efficient interaction of Ssb with the nascent chain.

    • Marie A. Hanebuth
    • , Roman Kityk
    •  & Elke Deuerling
  • Article
    | Open Access

    Small heat shock proteins (sHsps) contribute to cellular recovery and survival following stress causing elevated levels of misfolded or unfolded proteins. Here the authors demonstrate that sHsps function by maintaining aggregating proteins in close-to-native conformations to facilitate chaperone-mediated refolding.

    • Sophia Ungelenk
    • , Fatemeh Moayed
    •  & Bernd Bukau
  • Article
    | Open Access

    Pluripotent stem cells are thought to require a highly active proteostatic machinery. Here, the authors show that CCT8, a subunit of the proteostatic chaperonin complex, is increased in pluripotent stem cells, and that overexpression of CCT8 in worms increases cellular proteostasis and organismal longevity.

    • Alireza Noormohammadi
    • , Amirabbas Khodakarami
    •  & David Vilchez
  • Article
    | Open Access

    Cerebrovascular accumulation of Aβ is a common feature of Alzheimer’s disease, though it is unclear whether mutant vascular amyloid is capable of Aβ seeding. Here, the authors show microvascular amyloid seeds are capable of driving wild-type Aβ to assemble into distinctive anti-parallel fibrillary structures.

    • Feng Xu
    • , Ziao Fu
    •  & William E. Van Nostrand
  • Article
    | Open Access

    Some bacterial toxin-antitoxin systems consist of a labile antitoxin that inhibits a toxin, and a chaperone that stabilizes the antitoxin. Here, Bordes et al. identify a sequence within the antitoxin to which the chaperone binds and which can be transferred to other proteins to make them chaperone-dependent.

    • Patricia Bordes
    • , Ambre Julie Sala
    •  & Pierre Genevaux
  • Article
    | Open Access

    The β-barrel assembly machinery (BAM complex) is a key mediator of outer membrane protein biogenesis in Gram-negative bacteria. Here the authors report a cryo-EM structure of the intact BAM complex that suggests that lateral gate opening is a necessary part of the BAM functional cycle.

    • Matthew G. Iadanza
    • , Anna J. Higgins
    •  & Neil A. Ranson
  • Article
    | Open Access

    Building crystal structures into the electron density is an important step in protein structure solution. Here, the authors recruit online game players, students, and experienced crystallographers to compete in a competition to solve a new structure, and find that crowdsourcing model-building works.

    • Scott Horowitz
    • , Brian Koepnick
    •  & James C. A. Bardwell
  • Article
    | Open Access

    The elucidation of amyloid nucleation mechanisms remains challenging as early oligomeric intermediates are transient and difficult to distinguish. Here the authors use Aβ- polyglutamine hybrid peptides designed to slow and limit amyloid maturation to provide insights into the structures of Aβ self-assembly intermediates.

    • Pinaki Misra
    • , Ravindra Kodali
    •  & Ronald Wetzel