Protein folding

  • Article
    | Open Access

    The chlorosome of the photosynthetic bacterium C. tepidumharvests light and transfers the energy to the photosynthetic reaction centre. Here the authors determine the structure of the baseplate, a scaffolding super-structure, to show that the baseplate consists of rods of repeated CsmA dimers containing pigment molecules.

    • Jakob Toudahl Nielsen
    • , Natalia V. Kulminskaya
    •  & Niels Chr. Nielsen
  • Article
    | Open Access

    Switching target protein accumulation and activity by portable conditional degrons is potentially useful for both basic research and bioengineering. Here the authors present a versatile system to tune protein levels in live animals and plants using a temperature-sensitive N-end rule degradation signal.

    • Frederik Faden
    • , Thomas Ramezani
    •  & Nico Dissmeyer
  • Article
    | Open Access

    Aerolysin is a secreted bacterial pore forming toxin that inserts into the host plasma membrane, potentially leading to cell death. Here the authors present Cryo-EM structures of aerolysin arrested at different stages of the pore formation process that provide insight into the conformational changes that allow pore formation.

    • Ioan Iacovache
    • , Sacha De Carlo
    •  & Benoît Zuber
  • Article
    | Open Access

    Hsp90 is required for the folding, stability and activity of several drivers of oncogenesis. Here the authors show that Folliculin-interacting proteins (FNIP) 1 and 2, whose expression correlates with the cellular response to Hsp90 inhibitors, are co-chaperones of Hsp90 that function by inhibiting its ATPase activity.

    • Mark R. Woodford
    • , Diana M. Dunn
    •  & Mehdi Mollapour
  • Article
    | Open Access

    Previous investigations have indicated that the model protein CspB folds in a simple two-state fashion. Here, the authors provide direct experimental evidence for that the energy landscape of two-state folding proteins is highly heterogeneous and that unfolding can occur via multiple pathways.

    • Jörg Schönfelder
    • , Raul Perez-Jimenez
    •  & Victor Muñoz
  • Article
    | Open Access

    Protein aggregates are associated with a wide variety of diseases. Here, in order to address how protein aggregation affects cellular homoeostasis, the authors describe a method to rapidly create protein aggregates in living cells and organisms with precise spatial and temporal control.

    • Yusuke Miyazaki
    • , Kota Mizumoto
    •  & Thomas J. Wandless
  • Article
    | Open Access

    Mutations in pendrin, a plasma membrane transporter, lead to Pendred syndrome, which is associated with hearing loss. Here, Jung et al. show that cell-surface expression of a mutated form of pendrin can be restored by blocking ER-to-Golgi traffic and triggering a DNAJC14 dependent unconventional secretion pathway.

    • Jinsei Jung
    • , Jiyoon Kim
    •  & Min Goo Lee
  • Article
    | Open Access

    Kinase inhibitors are important drugs and usually target the ATP binding pocket of kinases. Here, Kii et al.report a completely new type of kinase inhibitor that specifically targets the protein folding intermediate state, but not the mature form, of the protein kinase DYRK1A.

    • Isao Kii
    • , Yuto Sumida
    •  & Masatoshi Hagiwara
  • Article
    | Open Access

    Protein aggregation plays a crucial role in several neurodegenerative diseases. Here the authors demonstrate that phosphorylation of β-amyloid aggregates—the pathological hallmark of Alzheimer's disease—can change the molecular properties of aggregates, suggesting how phosphorylation contributes to disease progression.

    • Nasrollah Rezaei-Ghaleh
    • , Mehriar Amininasab
    •  & Markus Zweckstetter
  • Article
    | Open Access

    Mutations in aggregation prone regions of recombinant proteins often improve their solubility, although they might cause negative effects on their structure and function. Here, the authors identify proteins hot spots that can be exploited to optimize solubility without compromising stability.

    • Ashok Ganesan
    • , Aleksandra Siekierska
    •  & Joost Schymkowitz
  • Article
    | Open Access

    The folding of protein domains can occur concomitant with their synthesis, and the rates at which individual codons are translated by the ribosome can affect the folding process. Here the authors present a kinetic model that accurately predicts the probability that a nascent protein domain will co-translationally fold in vivo.

    • Daniel A. Nissley
    • , Ajeet K. Sharma
    •  & Edward P. O’Brien
  • Article
    | Open Access

    Under stress conditions the molecular chaperone Hsp33 is activated to process unfolded proteins. Here, the authors use in vivo and in vitro crosslinking and 19F-NMR to elucidate the binding site for misfolded proteins and are able to propose a model for its mechanism of action.

    • Bastian Groitl
    • , Scott Horowitz
    •  & Ursula Jakob
  • Article
    | Open Access

    Amyloid-beta deposits are a pathological hallmark of Alzheimer’s disease, and have previously been targeted in immunisation therapies. Here, the authors show that oral administration of the small molecule EPPS reduces Aß plaque and oligomer load in APP/PS1 mice and improves learning and memory performance.

    • Hye Yun Kim
    • , Hyunjin Vincent Kim
    •  & YoungSoo Kim
  • Article
    | Open Access

    The bacterium Bdellovibrio bacteriovorus invades and kills other bacteria, but it is unclear how it avoids degradation of its own cell wall. Here the authors identify the B. bacteriovorusprotein Bd3460 as an endopeptidase inhibitor that prevents hydrolysis of the predator’s peptidoglycan during invasion of prey.

    • Carey Lambert
    • , Ian T. Cadby
    •  & Andrew L. Lovering
  • Article
    | Open Access

    Single molecule kinetics investigations and molecular simulations are useful tools in elucidating protein assembly mechanisms. Here, the authors use these to show that even naturally occurring tandem repeats undergo transient misfolding and that assembly is much more complex than we previously understood.

    • Alessandro Borgia
    • , Katherine R. Kemplen
    •  & Benjamin Schuler
  • Article
    | Open Access

    Hsp70 chaperones are essential for cellular proteostasis, and their function depends on allosteric communication between their nucleotide- and substrate-binding domains. Here, Kityk et al.provide a mechanical model of allostery and demonstrate that ATP-induced substrate release is more important for chaperone activity than substrate-stimulated ATP hydrolysis.

    • Roman Kityk
    • , Markus Vogel
    •  & Matthias P. Mayer
  • Article
    | Open Access

    In metalloproteins, a metal cofactor participates in the formation of the correct fold. Here the authors demonstrate—using single molecule force spectroscopy and the native copper centre as an embedded internal reporter—that the blue-copper proteins azurin and plastocyanin unfold via two independent competing pathways under force.

    • Amy E. M. Beedle
    • , Ainhoa Lezamiz
    •  & Sergi Garcia-Manyes
  • Article
    | Open Access

    In biological systems, large pH-induced conformational changes can be observed in certain proteins, a phenomenon poorly understood at the molecular level. Here the authors describe a peptide with the ability to self-organize into either small or large nanotubes in a pH-dependent manner and detail the mechanism driving the transition.

    • Céline Valéry
    • , Stéphanie Deville-Foillard
    •  & Franck Artzner
  • Article
    | Open Access

    Single molecule spectroscopy can visualise dynamic changes in protein conformation on the submillisecond timescale. Here, Otosu et al. apply two-dimensional fluorescence lifetime correlation spectroscopy to visualise dynamics between seven conformers of cytochrome con the microsecond timescale.

    • Takuhiro Otosu
    • , Kunihiko Ishii
    •  & Tahei Tahara
  • Article
    | Open Access

    The synthesis of ribosomes requires the orderly assembly of many proteins and large RNA molecules, a process that involves several assembly factors. Here the authors show that dedicated chaperones capture the N termini of specific nascent ribosomal proteins to promote folding and assembly into maturing ribosomes.

    • Patrick Pausch
    • , Ujjwala Singh
    •  & Dieter Kressler
  • Article
    | Open Access

    The twin-arginine translocation complex consists of TatA, TatB and TatC subunits and transports folded proteins across cellular membranes. Here, using photocrosslinking, the authors show that TatB monomers form dome-like structures that are surrounded by TatC monomers enabling lateral access of TatA.

    • Anne-Sophie Blümmel
    • , Laura A. Haag
    •  & Julia Fröbel
  • Article
    | Open Access

    The signal recognition particle plays a key role in the co-translational protein targeting of membrane and secretory proteins. Here the authors report a crystal structure of the ternary SRP complex in signal sequence bound and unbound forms, providing insight into how signal sequence binding is coupled to SRP receptor interaction.

    • Tobias Hainzl
    •  & A. Elisabeth Sauer-Eriksson
  • Article
    | Open Access

    Although most protein folding experiments can be explained by a single pathway, theoretical evidence suggests the presence of multiple pathways. Here, the authors resolve this using a combination of force, chemical denaturation and mutagenesis to modulate the flux between parallel pathways.

    • Emily J. Guinn
    • , Bharat Jagannathan
    •  & Susan Marqusee
  • Article |

    Phagocytic glia can internalize protein aggregates in vitro. Here Pearce et al. show in Drosophila that glia clear mutant huntingtin (Htt) aggregates in a scavenger receptor Draper-dependent manner in vivo, and that internalized Htt aggregates induce the prion-like conversion of wild-type Htt expressed in the glial cytoplasm.

    • Margaret M. P. Pearce
    • , Ellen J. Spartz
    •  & Ron R. Kopito
  • Article
    | Open Access

    The chaperones Hsp70 and Hsp90 are physically linked via the cochaperone Sti1/Hop, that has two binding sites for Hsp70. Here, Röhl et al.show that binding of Hsp90 changes the conformation of Sti1/Hop and determines to which site Hsp70 binds, perhaps facilitating transfer of client proteins from Hsp70 to Hsp90.

    • Alina Röhl
    • , Daniela Wengler
    •  & Johannes Buchner
  • Article
    | Open Access

    Heat shock induces proteotoxic stress, and the cellular response is mediated by heat-shock factor 1 (HSF1). Here, Tan et al.show that following heat shock, mitochondrial SSBP1 translocates to the nucleus and binds HSF1 to enhance the expression of chaperones and support the maintenance of mitochondrial function.

    • Ke Tan
    • , Mitsuaki Fujimoto
    •  & Akira Nakai
  • Article |

    Acyldepsipeptides are natural antibiotics that function by activating the ClpP protease and deregulating proteolysis. Here, Gersch et al.show that acyldepsipeptides not only increase access to the active sites but also exert conformational control, thereby allosterically stimulating ClpP catalysis.

    • Malte Gersch
    • , Kirsten Famulla
    •  & Stephan A. Sieber
  • Article |

    The bacterial Hsp70 chaperone system consists of DnaJ, DnaK and GrpE. To understand how these chaperones cooperate, Nunes et al. monitor refolding immunoglobulin domains using single-molecule force microscopy to demonstrate that the ‘holdase’ DnaJ can show foldase activity and suggest that GrpE can facilitate substrate release from DnaK.

    • João M. Nunes
    • , Manajit Mayer-Hartl
    •  & Daniel J. Müller
  • Article
    | Open Access

    Ubiquitin is a stable and soluble protein, but it is commonly found in inclusion bodies in neurodegenerative disorders and cancer. Here, Morimoto et al. report that increasing ubiquitin chain length leads to the formation of amyloid-like fibrils, which are degraded by an autophagy mechanism.

    • Daichi Morimoto
    • , Erik Walinda
    •  & Masahiro Shirakawa
  • Article |

    Small molecules that inhibit α-synuclein misfolding may have potential in the treatment of Parkinson’s disease. Fonseca-Ornelas et al.show that several of these molecules fail to block misfolding in the presence of membrane vesicles, and reveal how phtalocyanine tetrasulfonate, in contrast, overcomes this effect.

    • Luis Fonseca-Ornelas
    • , Sybille E. Eisbach
    •  & Markus Zweckstetter
  • Article |

    Scrapie, a form of prion disease that affects sheep and goats, is believed not to be transmissible to humans. Using transgenic mice expressing human prion protein as a model of cross-species prion transmission, the authors show that ovine scrapie may possess potential to be passed on to humans.

    • Hervé Cassard
    • , Juan-Maria Torres
    •  & Olivier Andréoletti
  • Article |

    Transmission of alpha-synuclein aggregates between neurons has been observed in animal models of Parkinson’s disease, however, the mechanism of transmission remains unclear. Bae et al. report that a cycle of uptake, co-aggregation and exocytosis is enhanced by loss of glucocerebrosidase activity.

    • Eun-Jin Bae
    • , Na-Young Yang
    •  & Seung-Jae Lee
  • Article |

    Uncontrolled calcium release from the endoplasmic reticulum results in cell death and toxicity. Here, the authors show that in neurons, stress induces the export of receptor-interacting protein 140 from the nucleus to the cytosol where it interacts with IP3Receptor, preventing its opening and the detrimental effects of calcium release.

    • Xudong Feng
    • , Kelly A. Krogh
    •  & Li-Na Wei
  • Article |

    While N-terminal acetylation has been shown to regulate the function or stability of a limited number of specific proteins, Holmes et al.report that global loss of this modification results in widespread protein misfolding, and show that the resulting stress response contributes to the suppression of a yeast prion phenotype.

    • William M. Holmes
    • , Brian K. Mannakee
    •  & Tricia R. Serio
  • Article |

    The yeast prion Sup35/[PSI+] confers a translation termination defect in its amyloid form. Pezza et al.reveal that aggregated Sup35 retains translation termination activity, and find that fluctuations in the size and composition of aggregates play an important role in determining their activity and toxicity.

    • John A. Pezza
    • , Janice Villali
    •  & Tricia R. Serio
  • Article
    | Open Access

    Prions (PrP) are infectious agents that cause lethal neurodegenerative diseases. Here the authors study the kinetics of prion propagation in mice and show that the onset of neuropathology occurs during the late phase of disease and is hypothesized to be due to increases in a toxic isoform of PrP that is different from the infectious species.

    • Malin K. Sandberg
    • , Huda Al-Doujaily
    •  & John Collinge
  • Article |

    The interaction of water molecules with a protein results in a frictional force that influences protein conformational dynamics and folding, though the nature of the protein also influences the friction. Here, the authors use molecular simulations to examine the origin of this protein contribution.

    • David de Sancho
    • , Anshul Sirur
    •  & Robert B. Best
  • Article |

    The activity of heat shock proteins (Hsp) is modified by binding to cochaperones. Here, the authors develop a four-colour FRET system to show that cochaperone p23 binding to Hsp90 strengthens the ATP-dependent directionality, thus validating their approach for the study of other multicomponent protein machines.

    • C. Ratzke
    • , B. Hellenkamp
    •  & T. Hugel
  • Article |

    α-synuclein is a protein whose aberrant aggregation is associated with Parkinson’s disease. Here, Fusco et al.characterize α-synuclein bound to lipid membranes using a combination of solution and solid-state NMR spectroscopy and provide insights into the molecular processes associated with the aggregation of this protein.

    • Giuliana Fusco
    • , Alfonso De Simone
    •  & Gianluigi Veglia
  • Article
    | Open Access

    Intracellular Aß oligomers have been linked to Alzheimer’s disease but details about their biosynthesis and function have been hard to obtain due to the lack of selective approaches for targeting them. Here, Meli et al.develop a strategy using recombinant antibodies to target Aß oligomers in the endoplasmic reticulum of cells, and perform mechanistic studies in cellular models of the disease.

    • Giovanni Meli
    • , Agnese Lecci
    •  & Antonino Cattaneo
  • Article
    | Open Access

    Misfolded protein accumulation is a hallmark of many neurodegenerative diseases. Here Budrikis et al. model protein aggregation in the endoplasmic reticulum and show that it is the result of a non-equilibrium phase transition caused by tipping the balance from the rates of protein production to degradation.

    • Zoe Budrikis
    • , Giulio Costantini
    •  & Stefano Zapperi
  • Article
    | Open Access

    Ire1 is an effector of the unfolded protein response that is activated upon stress to maintain protein homeostasis. Here, Prischi et al. demonstrate that phosphorylation of Ire1 within its kinase activation loop increases its RNAse activity, thus identifying a regulatory cross-talk between the two domains.

    • Filippo Prischi
    • , Piotr R. Nowak
    •  & Maruf M. U. Ali