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| 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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Article
| Open AccessCis P-tau is a central circulating and placental etiologic driver and therapeutic target of preeclampsia
Preeclampsia is the leading cause of maternal and fetal mortality worldwide. Here, the authors show that cis P-tau is a central circulating etiologic driver in preeclampsia and that the stereo-specific antibody targeting cis P-tau holds promise for early diagnosis and treatment of the disease.
- Sukanta Jash
- , Sayani Banerjee
- & Surendra Sharma
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Comment
| 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 AccessPolymorphic amyloid nanostructures of hormone peptides involved in glucose homeostasis display reversible amyloid formation
In this work, the authors highlight that conserved receptor binding segments of class B GPCR ligands have a dual nature: they serve as amyloid-prone regions involved in pH-dependent conversion from secretory amyloid fibrils to the functional folded form.
- Dániel Horváth
- , Zsolt Dürvanger
- & András Perczel
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Article
| Open AccessIntermediate filaments associate with aggresome-like structures in proteostressed C. elegans neurons and influence large vesicle extrusions as exophers
High neuronal proteostress can trigger the production of aggregate-filled exophers in C. elegans. Here authors show that such extrusion relies on aggregate-associated intermediate filaments and adaptors.
- Meghan Lee Arnold
- , Jason Cooper
- & Monica Driscoll
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Article
| Open AccessCryo-EM structure and polymorphic maturation of a viral transduction enhancing amyloid fibril
In this work, the authors report the Cryo-EM structure of PNF-18, a biotechnologically engineered peptide fibril that enhances retroviral infectivity. The peptide fibrils mature into polymorphic amyloid structures in a time-dependent manner. The structure provides insights into the molecular basis of peptide nanofibrils as retroviral transduction enhancers.
- Thomas Heerde
- , Desiree Schütz
- & Marcus Fändrich
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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 AccessFully co-factor-free ClearTau platform produces seeding-competent Tau fibrils for reconstructing pathological Tau aggregates
The authors report a method for producing co-factor-free fibrils from all full-length Tau isoforms. The method paves the way for reconstituting pathology resembling Tau fibrils and enables screening of Tau aggregation-modifying compounds for targeted therapies and PET tracers.
- Galina Limorenko
- , Meltem Tatli
- & Hilal A. Lashuel
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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 AccessMechanistic insights into the aggregation pathway of the patient-derived immunoglobulin light chain variable domain protein FOR005
Using solution-state NMR spectroscopy, the authors followed the individual steps involved in protein misfolding from the native to the amyloid fibril state for the antibody light chain (AL) amyloidosis related protein FOR005.
- Tejaswini Pradhan
- , Riddhiman Sarkar
- & Bernd Reif
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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 AccessIdentification of a covert evolutionary pathway between two protein folds
Protein secondary structures–α-helices and β-sheets–are generally assumed to be fixed over evolutionary history. By leveraging sequence information and sensitive statistical techniques, this work proposes that secondary structures in naturally occurring DNA-binding proteins switched in response to stepwise mutation.
- Devlina Chakravarty
- , Shwetha Sreenivasan
- & Lauren L. Porter
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Article
| Open AccessThe mechanisms to dispose of misfolded proteins in the endoplasmic reticulum of adipocytes
Endoplasmic reticulum (ER)-associated degradation (ERAD) and ER-phagy are two central degradative mechanisms in the ER. Here the authors describe the sequence of events underlying the disposition of misfolded ER proteins by ERAD and ER-phagy.
- Shuangcheng Alivia Wu
- , Chenchen Shen
- & Ling Qi
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Article
| Open AccessStacked binding of a PET ligand to Alzheimer’s tau paired helical filaments
Understanding the mode of small-molecule binding to amyloid filaments is critical for diagnosing and treating neurodegeneration. The authors use cryo-EM to reveal a stacked binding motif which may hasten design of diagnostics and therapeutics.
- Gregory E. Merz
- , Matthew J. Chalkley
- & Daniel R. Southworth
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Article
| Open AccessEarly events in amyloid-β self-assembly probed by time-resolved solid state NMR and light scattering
Here the authors report time-resolved experiments showing that amyloid-β peptide molecules become partially structured even before they adhere to one another, within one millisecond. Peptide conformations change only slightly as assemblies grow in size for many minutes.
- Jaekyun Jeon
- , Wai-Ming Yau
- & Robert Tycko
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Article
| Open AccessStructural analysis and architectural principles of the bacterial amyloid curli
Using Alpha fold modelling and cryo-EM reconstruction the authors reveal the structural and architectural principles of the bacterial functional amyloid curli, encompassing the continuous stacking of β-solenoid pseudo repeats within and across subunits.
- Mike Sleutel
- , Brajabandhu Pradhan
- & Han Remaut
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Article
| Open AccessArtificial Hsp104-mediated systems for re-localizing protein aggregates
Protein aggregates are a hallmark of neurodegenerative disease and aging. Here, Fischbach et al. report engineered, artificial systems to re-localise or export protein aggregates from cells, with preliminary data showing that mHtt inclusions in S. cerevisiae may be cytotoxic.
- Arthur Fischbach
- , Angela Johns
- & Thomas Nyström
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Article
| Open AccessImproving de novo protein binder design with deep learning
Recently, a pipeline for the design of protein-binding proteins using only the structure of the target protein was reported. Here, the authors report that the incorporation of deep learning methods into the original pipeline increases experimental success rate by ten-fold.
- Nathaniel R. Bennett
- , Brian Coventry
- & David Baker
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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 AccessCell surface-localized CsgF condensate is a gatekeeper in bacterial curli subunit secretion
In this work, the authors show that the phase separation of a cell surface-associated protein called CsgF is critical to mediate the secretion and assembly of the amyloidogenic curli subunits.
- Hema M. Swasthi
- , Joseph L. Basalla
- & Matthew R. Chapman
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Article
| Open AccessLow complexity domains of the nucleocapsid protein of SARS-CoV-2 form amyloid fibrils
Here, the authors show the amyloid formation of a low-complexity domain of NCAP, and its potential for guiding the design of antiviral agents.
- Einav Tayeb-Fligelman
- , Jeannette T. Bowler
- & David S. Eisenberg
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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 AccessGenipin prevents alpha-synuclein aggregation and toxicity by affecting endocytosis, metabolism and lipid storage
In this work, the authors identify Genipin as a small iridoid able to prevent alpha-synuclein aggregation and toxicity by affecting endocytosis, metabolism and lipid storage.
- Rita Rosado-Ramos
- , Gonçalo M. Poças
- & Cláudia N. Santos
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Article
| Open AccessFTD-tau S320F mutation stabilizes local structure and allosterically promotes amyloid motif-dependent aggregation
The authors used multi-disciplinary approaches to understand the structural mechanism underlying spontaneous aggregation of tau encoding an S320F FTD-tau mutant. Understanding the mechanisms of tau aggregation will help identify novel methods to regulate its misfolding.
- Dailu Chen
- , Sofia Bali
- & Lukasz A. Joachimiak
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Article
| Open AccessDisease-relevant β2-microglobulin variants share a common amyloid fold
The authors use cryo-EM to determine amyloid fibrils structures of disease relevant variants of β2-microglobulin in vitro. Each variant is polymorphic, but all polymorphs from all samples are built from a a lego-like assembly of common building blocks, suggesting a one amyloid fold’ paradigm.
- Martin Wilkinson
- , Rodrigo U. Gallardo
- & Neil A. Ranson
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Article
| Open AccessCell surface protein aggregation triggers endocytosis to maintain plasma membrane proteostasis
How cells respond to denaturation of extracellular protein domains remained largely unknown. Here, authors describe an aggregation-dependent endocytosis pathway, facilitating uptake and degradation of antibody- and stress-induced protein aggregates.
- David Paul
- , Omer Stern
- & Harvey McMahon
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Article
| Open AccessThe cofactor-dependent folding mechanism of Drosophila cryptochrome revealed by single-molecule pulling experiments
Characterizing folding pathways of large proteins that bind complex cofactors is challenging. The authors use optical tweezers to study the 542-residue FAD-binding lightsensor protein dCRY, identifying several intermediates and cofactor binding steps, and dissecting the role of FAD moieties in folding.
- Sahar Foroutannejad
- , Lydia L. Good
- & Rodrigo A. Maillard
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Article
| Open AccessSpatially confined protein assembly in hierarchical mesoporous metal-organic framework
Immobilization of biomolecules into porous materials could lead to enhanced performance in terms of stability and easier separation for their reuse. Here authors gain insights into the spatial arrangement of green fluorescent protein entrapped in a mesoporous MOF by situ small-angle neutron scattering.
- Xiaoliang Wang
- , Lilin He
- & Shengqian Ma
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Article
| Open AccessAmyloidogenic proteins in the SARS-CoV and SARS-CoV-2 proteomes
Bhardwaj et al., have explored the proteomes of SARS-CoV and SARS-CoV-2, and have demonstrated the amyloid formation of viral proteins, in vitro, through diverse biophysical techniques.
- Taniya Bhardwaj
- , Kundlik Gadhave
- & Rajanish Giri
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Article
| Open AccessNetwork of hotspot interactions cluster tau amyloid folds
The authors developed a computational approach to probe the stability of amyloid fibrils and discover networks of hotspot interactions. Understanding the mechanisms of amyloid folding will help identify novel methods to treat protein (mis)folding diseases.
- Vishruth Mullapudi
- , Jaime Vaquer-Alicea
- & Lukasz A. Joachimiak
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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 AccessRabphilin-3A undergoes phase separation to regulate GluN2A mobility and surface clustering
GluN2A and GluN2B, two predominant Glu2N subunits of NMDARs in hippocampus and cortex, display distinct organization and mobility in the neuronal surface. Here, authors show Rph3A, a GluN2A-specific binding protein, undergoes liquid-liquid phase separation, which regulate mobility, synaptic and extrasynaptic surface clustering, synaptic localization and synaptic response of GluN2A.
- Lei Yang
- , Mengping Wei
- & Chen Zhang
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Article
| Open AccessCryo-EM structure of hnRNPDL-2 fibrils, a functional amyloid associated with limb-girdle muscular dystrophy D3
The authors report the Cryo-EM of hnRNPDL-2 fibrils. The structure highlights features of a functional amyloid associated with limb-girdle muscular dystrophy-3 and explains how alternative splicing controls the assembly of this ribonucleoprotein.
- Javier Garcia-Pardo
- , Andrea Bartolomé-Nafría
- & Salvador Ventura
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Article
| Open AccessPQBP5/NOL10 maintains and anchors the nucleolus under physiological and osmotic stress conditions
The nucleolus is a liquid-liquid phase separation droplet that dynamically changes under stress. Here, the authors report PQBP5/NOL10 is a critical component of the nucleolus, maintaining its structure and position in the nucleus during osmotic stress.
- Xiaocen Jin
- , Hikari Tanaka
- & Hitoshi Okazawa
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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 AccessAmyloid fibril structure from the vascular variant of systemic AA amyloidosis
This study reports the cryo-EM structures of AA amyloid fibrils from two patients with vascular AA amyloidosis. The findings imply that different disease variants in systemic amyloidosis are associated with different fibril structures.
- Sambhasan Banerjee
- , Julian Baur
- & Marcus Fändrich
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Article
| Open AccessCryo-EM structure of ex vivo fibrils associated with extreme AA amyloidosis prevalence in a cat shelter
Here, the authors report the cryoEM structure of AA amyloid from a cat shelter with extreme disease prevalence and reveal the feline-specific sequence insert in the fibril core. The sequence is 99% identical to AA amyloid from cheetah with reported prion-like transmission in zoos.
- Tim Schulte
- , Antonio Chaves-Sanjuan
- & Stefano Ricagno
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Article
| Open AccessDOPAnization of tyrosine in α-synuclein by tyrosine hydroxylase leads to the formation of oligomers
In this work, the authors show that α-synuclein is posttranslationally dopanized at Tyr136 by tyrosine hydroxylase, which facilitates the formation of oligomers. This modification likely impacts pathogenesis and the selective degeneration of dopaminergic neurons in Parkinson’s disease.
- Mingyue Jin
- , Sakiko Matsumoto
- & Shinji Hirotsune
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Article
| Open AccessThe 3D structure of lipidic fibrils of α-synuclein
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
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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 AccessCryo-EM structure of an ATTRwt amyloid fibril from systemic non-hereditary transthyretin amyloidosis
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
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Article
| Open AccessTermination of the unfolded protein response is guided by ER stress-induced HAC1 mRNA nuclear retention
Chromatin remodeler Isw1 prevents export of maturing ribonucleoprotein particles. Here, the authors show that Isw1 inhibits the Unfolded Protein Response (UPR) from the nucleus by binding and restricting export of the mRNA encoding the main effector of UPR, thereby tuning adaptation to ER stress.
- Laura Matabishi-Bibi
- , Drice Challal
- & Anna Babour
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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 AccessScleral PERK and ATF6 as targets of myopic axial elongation of mouse eyes
he underlying mechanism of myopic axial elongation of the eyes has long been unknown. Here, the authors show that endoplasmic reticulum stress in the sclera and its sensor proteins, PERK and ATF6, are involved in myopic axial elongation
- Shin-ichi Ikeda
- , Toshihide Kurihara
- & Kazuo Tsubota
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Article
| Open AccessDe novo design of immunoglobulin-like domains
The immunoglobulin domain framework of antibodies has been a long standing design challenge. Here, the authors describe design rules for tailoring these domains and show they can be accurately designed, de novo, with high stability and the ability to scaffold functional loops.
- Tamuka M. Chidyausiku
- , Soraia R. Mendes
- & Enrique Marcos
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Perspective
| Open AccessProtein condensation diseases: therapeutic opportunities
In this review, the authors define protein condensation diseases as conditions caused by aberrant liquid-like or solid-like states of proteins, and describe opportunities for therapeutic interventions to restore the normal phase behaviour of proteins. The review accompanies the related collection of articles published in Nature Communications focusing on possible therapeutic approaches involving liquid-liquid phase separation.
- Michele Vendruscolo
- & Monika Fuxreiter
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Article
| Open AccessSmall soluble α-synuclein aggregates are the toxic species in Parkinson’s disease
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
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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