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| Open AccessChp1 is a dedicated chaperone at the ribosome that safeguards eEF1A biogenesis
Here the authors discover a dedicated ribosome-associated chaperone, Chp1, that assists in the challenging biogenesis of eukaryotic translation elongation factor 1A (eEF1A) by cotranslationally stabilizing the growing GTPase domain of eEF1A.
- Melania Minoia
- , Jany Quintana-Cordero
- & Claes Andréasson
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Article
| Open AccessA structural vista of phosducin-like PhLP2A-chaperonin TRiC cooperation during the ATP-driven folding cycle
Proper cellular proteostasis requires a network of the chaperonin TRiC/CCT with cochaperones prefoldin (PFD) and phosducin-like proteins (PhLPs) to facilitate the folding of essential eukaryotic proteins. Here, the authors characterized the ATP-driven cycle of TRiC-PFD-PhLP2A interaction using cryoEM and biochemical analyses.
- Junsun Park
- , Hyunmin Kim
- & Soung-Hun Roh
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Article
| Open AccessIdentification of potential aggregation hotspots on Aβ42 fibrils blocked by the anti-amyloid chaperone-like BRICHOS domain
This study identifies potential aggregation hotspots on the fibril surface of Alzheimer’s disease associated Aβ42 fibrils, which are blocked by the anti-amyloid chaperone-like domain BRICHOS.
- Rakesh Kumar
- , Tanguy Le Marchand
- & Axel Abelein
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Article
| Open AccessFolding pathway of a discontinuous two-domain protein
Here, using single molecule FRET, the unfolding and folding of a discontinuous two-domain protein was studied. The authors find that a dynamic, intermediate population entropically limits the rate of folding while the order of domain folding is kept in a slow-folding mutant.
- Ganesh Agam
- , Anders Barth
- & Don C. Lamb
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Article
| Open AccessStructure of the M. tuberculosis DnaK−GrpE complex reveals how key DnaK roles are controlled
Cryo-EM analysis reveals that the GrpE dimer of M. tuberculosis undergoes ratcheting motions when bound to an intact DnaK, thereby allosterically regulating DnaK’s nucleotide exchange and substrate release.
- Xiansha Xiao
- , Allison Fay
- & Huilin Li
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Article
| Open AccessCochaperones convey the energy of ATP hydrolysis for directional action of Hsp90
The precise role of cochaperones and ATP hydrolysis in driving Hsp90’s chaperone cycle is largely unclear. Here, the authors use single-molecule FRET to show that several cochaperones are necessary to establish directionality in Hsp90’s conformational cycle.
- Leonie Vollmar
- , Julia Schimpf
- & Thorsten Hugel
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Article
| Open AccessDynamic stability of Sgt2 enables selective and privileged client handover in a chaperone triad
Newly synthesized tail-anchored membrane proteins (TAs) are relayed in a chaperone triad, Hsp70, Sgt2, and Get3, for delivery to the endoplasmic reticulum. Here, the authors show how the conformational dynamics of the cochaperone Sgt2 generates a decision point to enable efficient and selective TA targeting.
- Hyunju Cho
- , Yumeng Liu
- & Shu-ou Shan
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Article
| Open AccessDNAJB6 mutants display toxic gain of function through unregulated interaction with Hsp70 chaperones
Here the authors characterize DNAJB6 mutants found in LGMDD1 patients. They show that these mutants retain aggregation-prevention activity, but have impaired regulation of Hsp70 binding, uncontrollably recruiting Hsp70s, depleting the chaperone levels and disrupting proteostasis.
- Meital Abayev-Avraham
- , Yehuda Salzberg
- & Rina Rosenzweig
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Article
| Open AccessThe self-association equilibrium of DNAJA2 regulates its interaction with unfolded substrate proteins and with Hsc70
J-domain proteins (JDPs) regulate Hsp70 function and specificity. Here, authors combine functional assays and cryoEM to describe the structure of a dynamic tubular assembly of DNAJA2, a class A JDP, and its stabilizing interdomain interactions.
- Lorea Velasco-Carneros
- , Jorge Cuéllar
- & Arturo Muga
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| Open AccessEpichaperomics reveals dysfunctional chaperone protein networks
Molecular chaperones establish essential protein-protein interaction networks. Modified versions of these assemblies are generally enriched in certain maladies. A study published in Nature Communications used epichaperomics to identify unique changes occurring in chaperone-formed protein networks during mitosis in cancer cells.
- Mark R. Woodford
- , Dimitra Bourboulia
- & Mehdi Mollapour
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Article
| Open AccessImmunoproteasome-specific subunit PSMB9 induction is required to regulate cellular proteostasis upon mitochondrial dysfunction
Mitochondrial dysfunction results in the accumulation of mitochondrial proteins in the cytosol. Here, the authors show that the immunoproteasome subunit PSMB9 promotes protein degradation to maintain cellular protein homeostasis.
- Minji Kim
- , Remigiusz A. Serwa
- & Agnieszka Chacinska
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Article
| Open AccessSystems-level analyses of protein-protein interaction network dysfunctions via epichaperomics identify cancer-specific mechanisms of stress adaptation
Epichaperomics allow the study of protein-protein interactions and their alterations, but probes have been limited to capturing HSP90 epichaperomes. Here, the authors introduce and validate a toolset of HSP70 epichaperome ligands, and use them in epichaperomics to identify a mechanism with which cancer cells can enhance the fitness of mitotic protein networks.
- Anna Rodina
- , Chao Xu
- & Gabriela Chiosis
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Article
| Open AccessHow soluble misfolded proteins bypass chaperones at the molecular level
How soluble misfolded proteins can bypass chaperones is unknown. Utilizing a meta-analysis, multi-scale modelling, and new experimental data it is found that this phenomena is common and arises from misfolded states that are native-like and long-lived due to protein self-entanglements.
- Ritaban Halder
- , Daniel A. Nissley
- & Edward P. O’Brien
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Article
| Open AccessCo-translational binding of importins to nascent proteins
Importins are known to facilitate nucleocytoplasmic transport and cytoplasmic chaperoning of some proteins. Here, the authors uncover that these proteins also act as co-translational chaperones for specific sets of proteins, for example ribonucleic acid binding factors.
- Maximilian Seidel
- , Natalie Romanov
- & Martin Beck
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Article
| Open AccessA first-in-class inhibitor of Hsp110 molecular chaperones of pathogenic fungi
Hsp110 chaperones play important roles in protein homeostasis in eukaryotes. Here, the authors identify a small compound that inhibits fungal Hsp110s as well as the growth and viability of the pathogenic fungus Candida albicans, supporting Hsp110s as targets for development of new antifungal drugs.
- Liqing Hu
- , Cancan Sun
- & Qinglian Liu
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Article
| Open AccessNucleotide exchange is sufficient for Hsp90 functions in vivo
A complete understanding of the role of ATP hydrolysis in Hsp90 function is elusive. Here, the authors show that ATP hydrolysis, but not binding, is dispensable for essential or specialized Hsp90 functions in vivo, shedding new light on this mystery.
- Michael Reidy
- , Kevin Garzillo
- & Daniel C. Masison
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Article
| Open AccessHsp90 provides a platform for kinase dephosphorylation by PP5
PP5 requires the molecular chaperone Hsp90 to dephosphorylate CRaf kinase and the Hsp90 cochaperone Cdc37. Here, authors show how Hsp90 acts as a platform to allow for targeted dephosphorylation by PP5.
- Maru Jaime-Garza
- , Carlos A. Nowotny
- & David A. Agard
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Article
| Open AccessStructural basis of impaired disaggregase function in the oxidation-sensitive SKD3 mutant causing 3-methylglutaconic aciduria
Mitochondrial SKD3 is an essential protein disaggregase. Here, authors solve the X-ray structures of SKD3Ank domain suggesting that the disease-associated mutation Y272C leads to a disulfide bond formation that impairs SKD3 function under oxidizing conditions.
- Sukyeong Lee
- , Sang Bum Lee
- & Francis T. F. Tsai
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Article
| Open AccessThe AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds in a cellular system
Tau aggregates are associated with several neurodegenerative disorders. In this work, I. Saha and colleagues show that valosin-containing protein (VCP) recruited to Tau fibrils disaggregates them. However, this process comes at a cost: it generates seeding-active Tau species as byproduct.
- Itika Saha
- , Patricia Yuste-Checa
- & Mark S. Hipp
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Article
| Open AccessThe mitochondrial Hsp70 controls the assembly of the F1FO-ATP synthase
The mitochondrial ATP synthase produces the bulk of cellular ATP. Here, the authors report a function of the mitochondrial Hsp70 in the formation of the catalytical head and in its assembly with the peripheral stalk to form the mature ATP synthase.
- Jiyao Song
- , Liesa Steidle
- & Thomas Becker
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Article
| Open AccessHSP90-CDC37-PP5 forms a structural platform for kinase dephosphorylation
Binding to HSP90-CDC37 is essential for the activity of many protein kinases, but its function is unclear. Here, the authors show that HSP90-CDC37 provides a structural platform for the phosphatase PP5 to dephosphorylate a bound kinase, ‘factory resetting’ it prior to release.
- Jasmeen Oberoi
- , Xavi Aran Guiu
- & Laurence H. Pearl
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Article
| Open AccessStructural dynamics of AAA + ATPase Drg1 and mechanism of benzo-diazaborine inhibition
Drg1 is a cytoplasmic AAA + ATPase responsible for releasing Rlp24 during ribosome assembly. Here, the authors show that Drg1 structurally and functionally shares many regulatory features with that of Cdc48/p97, suggesting a unfoldase role for Drg1.
- Chengying Ma
- , Damu Wu
- & Ning Gao
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Article
| Open AccessCooperative assembly of p97 complexes involved in replication termination
This study describes how p97Ufd1-Npl4 and the UBA-UBX protein Ubxn7 disassemble vertebrate replisomes during replication termination, and it provides novel insights into how p97 complexes assemble with UBA-UBX proteins on ubiquitylated substrates
- Olga V. Kochenova
- , Sirisha Mukkavalli
- & Johannes C. Walter
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Article
| Open AccessTranslational reprogramming in response to accumulating stressors ensures critical threshold levels of Hsp90 for mammalian life
The molecular chaperone Hsp90 decreases with age but whether organisms can physiologically tune expression is unclear. Here, the authors show that mammalian cells can adjust Hsp90 levels to accumulating cellular stress by translational reprogramming.
- Kaushik Bhattacharya
- , Samarpan Maiti
- & Didier Picard
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Article
| Open AccessStructural mechanism of tapasin-mediated MHC-I peptide loading in antigen presentation
The catalytic chaperone tapasin assists peptide loading onto MHC-I molecules for antigen presentation and immune recognition. Here, the authors present crystal structures that provide insights into the molecular mechanism of tapasin-mediated peptide exchange.
- Jiansheng Jiang
- , Daniel K. Taylor
- & Kannan Natarajan
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Article
| Open AccessMolecular basis of MHC I quality control in the peptide loading complex
The immune system monitors the health status of cells by surveilling fragments of foreign molecules from invaders presented on MHC I complexes at the cell surface. Here, the authors investigate the sequence of events of MHC I assembly and quality control cycle.
- Alexander Domnick
- , Christian Winter
- & Robert Tampé
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Article
| Open AccessIdentification 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
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Article
| Open AccessA 33-residue peptide tag increases solubility and stability of Escherichia coli produced single-chain antibody fragments
Low solubility and stability of Escherichia coli produced single chain variable fragments (scFvs) restrict their applications. Here the authors report a 33-residue peptide tag which simultaneously increases the solubility and thermostability of multiple scFvs produced in Escherichia coli SHuffle strain.
- Yang Wang
- , Wenjie Yuan
- & Yong-Xiang Wang
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Article
| Open AccessDisease-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
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Article
| Open AccessTrigger 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
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Article
| Open AccessCoordination 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
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Article
| Open AccessStructural 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
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Article
| Open AccessInsights 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
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Article
| Open AccessStress-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
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Article
| Open AccessThree-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
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Article
| Open AccessHidden 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
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Article
| Open AccessMapping 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
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Article
| Open AccessCyclophilin 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
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Article
| Open AccessTousled-like kinase 2 targets ASF1 histone chaperones through client mimicry
Tousled-like kinase 2 (TLK2) phosphorylates ASF1 histone chaperones to promote nucleosome assembly in S phase. Here, the authors show that TLK2 targets ASF1 by simulating its client protein histone H3, exploiting a primordial protein interaction surface for regulatory control.
- Bertrand Simon
- , Hua Jane Lou
- & David A. Calderwood
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Article
| Open AccessDifferential 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
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Article
| Open AccessTwo-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
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Article
| Open AccessPhosphorylation 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
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Article
| Open AccessThe 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
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Article
| Open AccessA general approach to protein folding using thermostable exoshells
In vitro protein folding can often result in aggregation and low yields. Here the authors use nanoscale exoshells to improve soluble yield, functional yield and specific activity of folded proteins.
- Samira Sadeghi
- , Siddharth Deshpande
- & Chester L. Drum
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Article
| Open AccessPathway of Hsp70 interactions at the ribosome
Here, the authors use in vivo site-specific crosslinking to provide molecular-level insight into how the fungal Hsp70 chaperone system — the Ssb:Ssz1:Zuo1 triad — assists the folding process for the nascent peptide chain emerging from the ribosome tunnel.
- Kanghyun Lee
- , Thomas Ziegelhoffer
- & Elizabeth A. Craig
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Article
| Open AccessDnaJC7 binds natively folded structural elements in tau to inhibit amyloid formation
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
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Article
| Open AccessStructures of a deAMPylation complex rationalise the switch between antagonistic catalytic activities of FICD
The ER chaperone BiP is regulated by FICD-mediated AMPylation and deAMPylation. Here, the authors characterise the structure of mammalian AMPylated BiP bound to FICD, by X-ray crystallography and neutron scattering, providing insights into the mechanism of BiP AMPylation and deAMPylation.
- Luke A. Perera
- , Steffen Preissler
- & David Ron
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Article
| Open AccessThe extracellular chaperone Clusterin enhances Tau aggregate seeding in a cellular model
Variants of the extracellular chaperone Clusterin are associated with Alzheimer’s disease (AD) and Clusterin levels are elevated in AD patient brains. Here, the authors show that Clusterin binds to oligomeric Tau, which enhances the seeding capacity of Tau aggregates upon cellular uptake. They also demonstrate that Tau/Clusterin complexes enter cells via the endosomal pathway, resulting in damage to endolysosomes and entry into the cytosol, where they induce the aggregation of endogenous, soluble Tau.
- Patricia Yuste-Checa
- , Victoria A. Trinkaus
- & F. Ulrich Hartl
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Article
| Open AccessThe HSP90/R2TP assembly chaperone promotes cell proliferation in the intestinal epithelium
RPAP3 is a subunit of the R2TP complex, a co-chaperone of HSP90, with substrate proteins involved in transcription, ribosome biogenesis, DNA repair and cell growth. Here the authors report that deletion of Rpap3 abrogates cell proliferation and homeostasis in mouse intestine, partly through destabilization of PI3K-like kinases, while elevated RPAP3 levels in colorectal tumors are associated with poor prognosis.
- Chloé Maurizy
- , Claire Abeza
- & Bérengère Pradet-Balade