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| Open AccessStructures of human prostaglandin F2α receptor reveal the mechanism of ligand and G protein selectivity
Cryo-EM structures reveal the molecular mechanism of ligands and G protein selectivity for prostaglandin F2α receptor, providing guidance for development of better postpartum hemorrhage drugs.
- Xiuqing Lv
- , Kaixuan Gao
- & Xiangyu Liu
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Article
| Open AccessCharacterization of nucleolar SUMO isopeptidases unveils a general p53-independent checkpoint of impaired ribosome biogenesis
Ribosome biogenesis is tightly coordinated with cell-cycle progression. By characterizing the SUMO isopeptidases SENP3/SENP5, Doenig et al. identify a long-sought p53-independent impaired ribosome checkpoint that converges on downregulation of CDK6.
- Judith Dönig
- , Hannah Mende
- & Stefan Müller
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Article
| Open AccessPhospholipids are imported into mitochondria by VDAC, a dimeric beta barrel scramblase
Mitochondria depend on phospholipids supplied by the endoplasmic reticulum. Here, using biochemical assays and molecular dynamics simulations, authors identify VDAC as a scramblase-type lipid transporter that catalyze lipid entry.
- Helene Jahn
- , Ladislav Bartoš
- & Anant K. Menon
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Article
| Open AccessTransmembrane coupling of liquid-like protein condensates
Using a freestanding planar lipid membrane system, the authors show that liquid-like protein condensates on one side of a lipid membrane colocalize with those on the opposite side, suggesting a mechanism of information transfer across biological membranes.
- Yohan Lee
- , Sujin Park
- & Jeanne C. Stachowiak
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Article
| Open AccessStructural basis of antibody inhibition and chemokine activation of the human CC chemokine receptor 8
CCR8 is a promising target in cancer immunotherapy. Here, authors generated mAb1, an antagonist antibody against CCR8 and determined structures of CCR8 in complex with mAb1 or the agonist CCL1, providing insights into CCR8 inhibition and activation.
- Dawei Sun
- , Yonglian Sun
- & Matthieu Masureel
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Matters Arising
| Open AccessReply to: How carvedilol does not activate β2-adrenoceptors
- Evi Kostenis
- , Jesus Gomeza
- & Stefan Schulz
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Article
| Open AccessDistinct activation mechanisms of β-arrestin-1 revealed by 19F NMR spectroscopy
The molecular basis for the functional versatility of β-arrestins in the G-protein coupled receptor signaling pathway is not well understood. Here, the authors use19F NMR spectroscopy to show that different binding partners activate β-arrestin-1 through distinct mechanisms.
- Ruibo Zhai
- , Zhuoqi Wang
- & Yunfei Hu
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Article
| Open AccessDiscovery of a novel cardiac-specific myosin modulator using artificial intelligence-based virtual screening
Modulation of the myosin molecular motor has emerged as a potential therapeutic target for both heart disease and heart failure. Here, the authors use AI-based virtual high throughput screening to identify compounds that acts as a cardiac-specific myosin modulators.
- Priyanka Parijat
- , Seetharamaiah Attili
- & Thomas Kampourakis
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Article
| Open AccessBioE3 identifies specific substrates of ubiquitin E3 ligases
Here, the authors describe BioE3, a biotin-based method to discriminate direct substrates of ubiquitin E3 ligases of interest from mere interactors using proximity proteomics. BioE3 responds to chemical treatments, and works with RING- and HECT-type E3s, as well as ubiquitin-likes (e.g., SUMO).
- Orhi Barroso-Gomila
- , Laura Merino-Cacho
- & James D. Sutherland
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Article
| Open AccessOrthosteric and allosteric modulation of human HCAR2 signaling complex
Hydroxycarboxylic acid receptor 2 (HCAR2) has been implicated in cardiovascular and neuroinflammatory diseases. Here, the authors present cryo-EM structures of HCAR2-Gi1 complexes bound to different ligands and provide insights into the mechanisms of both orthosteric and allosteric modulation of HCAR2.
- Chunyou Mao
- , Mengru Gao
- & Yan Zhang
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Article
| Open AccessActivation and substrate specificity of the human P4-ATPase ATP8B1
Asymmetric phospholipid distribution in cell membranes is vital for cellular function. Here, authors reveal how ATP8B1, a P4-ATPase, can transport different lipids, including phosphatidylinositol.
- Thibaud Dieudonné
- , Felix Kümmerer
- & Poul Nissen
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Article
| Open AccessThe GET insertase exhibits conformational plasticity and induces membrane thinning
Tail-anchored (TA) membrane protein biogenesis is mediated by the GET insertase. Here, authors present cryo-EM and X-ray structures, MD simulations and functional data for human and fungal insertases showing membrane remodeling for TA insertion.
- Melanie A. McDowell
- , Michael Heimes
- & Irmgard Sinning
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Article
| Open AccessStructural basis of bile salt extrusion and small-molecule inhibition in human BSEP
BSEP (ABCB11) is expressed in hepatocytes and extrudes bile salts into the canaliculi of the liver. Here, authors report cryo-EM structures of BSEP providing structural and functional insight into the mechanism of bile salt extrusion and small-molecule inhibition.
- Hongtao Liu
- , Rossitza N. Irobalieva
- & Kaspar P. Locher
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Article
| Open AccessMultiple E3 ligases control tankyrase stability and function
The poly(ADP-ribosyl)transferases, tankyrase 1 and 2, are regulated by RNF146-mediated K48-linked polyubiquitylation and degradation. Here the authors show that this is opposed by K11-linked diubiquitylation by RING-UIM E3 ligases RNF114 and 166 and further impacted by several PAR-binding E3 ligases.
- Jerome Perrard
- & Susan Smith
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Article
| Open AccessC-terminal modification and functionalization of proteins via a self-cleavage tag triggered by a small molecule
Specific modification or functionalization of proteins at the C-terminus is of interest but remains challenging. Here, the authors report an approach for the efficient modification of C-terminus by fusion of the cysteine protease domain (CPD) on the C-terminus of the protein of interest, and subsequent functionalization with amine-containing molecules triggered by InsP6-mediated CPD self-cleavage.
- Yue Zeng
- , Wei Shi
- & Feng Tang
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Article
| Open AccessStructural basis for ligand recognition and signaling of hydroxy-carboxylic acid receptor 2
Niacin is used to treat cardiovascular disease through its activation of the GPCR HCAR2. Here, the authors present cryo-EM structures of HCAR2 bound to niacin and other drug-like small molecules, which explain the basis of HCAR2 ligand recognition.
- Jae-Hyun Park
- , Kouki Kawakami
- & Sam-Yong Park
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Article
| Open AccessA TRIM21-based bioPROTAC highlights the therapeutic benefit of HuR degradation
Overexpression of human antigen R (HuR) correlates with high grade tumours and poor patient prognosis. Here, the authors engineer a TRIM21 biological PROTAC to demonstrate the benefit of a targeted protein degradation approach to deplete HuR, resulting in tumour growth inhibition in pre-clinical cancer models by altering the HuR-regulated proteome.
- Alice Fletcher
- , Dean Clift
- & James Hunt
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Article
| Open AccessStructure of a membrane-bound menaquinol:organohalide oxidoreductase
The structure of a bacterial membrane protein complex involved in the bioremediation of tetrachloroethene, a major chlorinated organic pollutant, was determined. It elucidates the path of electrons from menaquinol to the active site of the enzyme.
- Lorenzo Cimmino
- , Américo G. Duarte
- & Julien Maillard
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Article
| Open AccessA marine cryptochrome with an inverse photo-oligomerization mechanism
Cryptochromes are important components of biological clocks. Here, the authors uncover that a cryptochrome that enables synchronization of the reproduction of marine worms to the lunar cycle uses an inverse photo-oligomerization mechanism.
- Hong Ha Vu
- , Heide Behrmann
- & Elmar Behrmann
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Article
| Open AccessStructural titration reveals Ca2+-dependent conformational landscape of the IP3 receptor
Inositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular Ca2+ channels that produce Ca2+ oscillations in response to GPCR and RTK activation. Here, Paknejad et al. resolve the conformational landscape of IP3Rs that gives rise to the biphasic dependence on Ca2+ for channel activity.
- Navid Paknejad
- , Vinay Sapuru
- & Richard K. Hite
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Article
| Open AccessFolding correctors can restore CFTR posttranslational folding landscape by allosteric domain–domain coupling
The conformational biogenesis of multi-domain ABC-transporters is poorly understood. Here the authors show the critical role of dynamic allosteric coupling networks, its perturbation and restoration in CFTR folding, misfolding, and pharmacological rescue, respectively.
- Naoto Soya
- , Haijin Xu
- & Gergely L. Lukacs
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Article
| Open AccessN-terminal acetylation shields proteins from degradation and promotes age-dependent motility and longevity
The most common protein modification in eukaryotes is N-terminal acetylation, but its functional impact has remained enigmatic. Here, the authors find that a key role for N-terminal acetylation is shielding proteins from ubiquitin ligase-mediated degradation, mediating motility and longevity.
- Sylvia Varland
- , Rui Duarte Silva
- & Thomas Arnesen
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Article
| Open AccessDynamic interactions between E-cadherin and Ankyrin-G mediate epithelial cell polarity maintenance
The maintenance of cell polarity depends on adhesion complexes that tether to the cytoskeleton. Here the authors show the dynamic nature of E-cadherin–Ankyrin-G complex formation and investigate its functional role in epithelial cell polarity maintenance.
- Chao Kong
- , Xiaozhan Qu
- & Chao Wang
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Article
| Open AccessDynamic characterization and interpretation for protein-RNA interactions across diverse cellular conditions using HDRNet
Predicting dynamic RNA-RBP interactions in diverse cell lines is an important challenge in unravelling RNA function and post-transcriptional regulatory mechanisms. Here, authors develop HDRNet, an end-to-end deep-learning-based framework for accurately predicting dynamic RBP binding events across various cellular conditions.
- Haoran Zhu
- , Yuning Yang
- & Xiangtao Li
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Article
| Open AccessFood amyloid fibrils are safe nutrition ingredients based on in-vitro and in-vivo assessment
Food protein amyloid fibrils have superior properties but due to safety concerns, have not yet been used in foods. In-vitro and in-vivo studies here show that upon digestion they are safe and can be used as potential ingredients for human nutrition.
- Dan Xu
- , Jiangtao Zhou
- & Raffaele Mezzenga
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Article
| Open AccessStructural insights into the agonists binding and receptor selectivity of human histamine H4 receptor
Histamine receptor H4R is implicated in chronic inflammatory diseases, such as asthma, arthritis, and atopic dermatitis. Here, the authors determined the first cryo-EM structure of the histamine H4 receptor, providing valuable structural insights for the design of drugs targeting H4R in chronic inflammatory diseases.
- Dohyun Im
- , Jun-ichi Kishikawa
- & So Iwata
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Article
| Open AccessFibrocystin/Polyductin releases a C-terminal fragment that translocates into mitochondria and suppresses cystogenesis
Fibrocystin/Polyductin (FPC) is a large ciliary membrane protein encoded by PKHD1 which, when mutated, causes ARPKD. Here, the authors show that FPC suppresses cyst development in the kidney of mouse models through the release and mitochondrial translocation of its C terminal product.
- Rebecca V Walker
- , Qin Yao
- & Feng Qian
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Article
| Open AccessStructural basis of dimerization of chemokine receptors CCR5 and CXCR4
Here, authors report chemokine receptors structures obtained using coarse-grained metadynamics. CCR5 and CXCR4 homo- and heterodimers differ in the conformations of ligand binding sites and of the G protein interaction interface, suggesting structural basis for the rational design of biased ligands.
- Daniele Di Marino
- , Paolo Conflitti
- & Vittorio Limongelli
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Article
| Open AccessStructural basis for triacylglyceride extraction from mycobacterial inner membrane by MFS transporter Rv1410
Triacylglycerides help to secure the impermeability of mycobacterial cell envelope to some drugs. Here, authors solve the structure of the triacylglyceride transporter Rv1410 and proposed a molecular mechanism for triacylglyceride extraction.
- Sille Remm
- , Dario De Vecchis
- & Markus A. Seeger
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Article
| Open AccessUSP36 stabilizes nucleolar Snail1 to promote ribosome biogenesis and cancer cell survival upon ribotoxic stress
Targeting ribosome biogenesis with the ribosome inhibitor, homoharringtonine (HHT), is effective in leukaemia but not in solid tumours. Here, the authors demonstrate that in solid tumours, activation of JNK signaling following HHT-induced ribosomal stress promotes Snail1 accumulation in the nucleolus which facilitates ribosome biogenesis and resistance to HHT.
- Kewei Qin
- , Shuhan Yu
- & Yong Yi
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Article
| Open AccessIntegrative solution structure of PTBP1-IRES complex reveals strong compaction and ordering with residual conformational flexibility
An integrated structural biology approach is utilized to elucidate the solution structure of the polypyrimidine-tract binding protein 1 (PTBP1/hnRNP I) complexed with an internal ribosome entry site (IRES) RNA fragment from encephalomyocarditis virus (EMCV).
- Georg Dorn
- , Christoph Gmeiner
- & Frédéric H.-T. Allain
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Article
| Open AccessStructure of full-length cobalamin-dependent methionine synthase and cofactor loading captured in crystallo
Methionine synthase (MS) harnesses B12 and flexibility to catalyze three different reactions on one protein. The full-length structure of MS yields insights into a protein that epitomizes controlled dynamics to dictate chemical outcome.
- Johnny Mendoza
- , Meredith Purchal
- & Markos Koutmos
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Article
| Open AccessC9orf72-catalyzed GTP loading of Rab39A enables HOPS-mediated membrane tethering and fusion in mammalian autophagy
The HOPS complex mediates membrane tethering and autophagosome-lysosome fusion. Here, the authors biochemically reconstitute the mammalian HOPS in protoliposomes and propose a model of complex assembly that depends on Rab2 and Rab39A.
- Shen Zhang
- , Mindan Tong
- & Qing Zhong
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Article
| Open AccessGLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics
Agonists of the glucagon-like peptide-1 receptor are used to treat diabetes and obesity. Here, Wright et al. investigate the subcellular location of the receptor’s signaling events and uncover associations between signaling profiles and adverse drug reactions.
- Shane C. Wright
- , Aikaterini Motso
- & Volker M. Lauschke
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Article
| Open AccessStructural conservation of insulin/IGF signalling axis at the insulin receptors level in Drosophila and humans
Insulin hormones and their receptors regulate key life processes in animals: from metabolism to life span. Human insulin receptor has been studied extensively. Here, the authors show remarkable structural similarity of fruit fly and human insulin receptors, indicating their universal functioning.
- Cristina M. Viola
- , Orsolya Frittmann
- & Andrzej M. Brzozowski
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Article
| Open AccessStructural insights into the conformational changes of BTR1/SLC4A11 in complex with PIP2
BTR1 is an electrogenic H+ transporter belonging to the bicarbonate transporter family. Here, the authors present structures of BTR1 in different conformations and uncover PIP2 as the activator of BTR1.
- Yishuo Lu
- , Peng Zuo
- & Yuxin Yin
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Article
| Open AccessAn autoinhibited state of 53BP1 revealed by small molecule antagonists and protein engineering
Here, using small molecule antagonists and protein engineering, the authors identify an autoinhibited state of 53BP1 leading to its chromatin binding surface being obstructed. Such small molecule ligands present a potential avenue for the development of cancer therapy drugs.
- Gaofeng Cui
- , Maria Victoria Botuyan
- & Georges Mer
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Article
| Open AccessNLRP6 potentiates PI3K/AKT signalling by promoting autophagic degradation of p85α to drive tumorigenesis
The crosstalk between innate immunity and autophagy plays a critical role in cancer. Here, the authors report that an immune receptor NLRP6 potentiates the PI3K/AKT pathway by selective degradation of p85α. The NLRP6-p85α interaction offers a potential therapeutic target for tumor treatment.
- Feng Zhi
- , Bowen Li
- & Jun Cui
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Article
| Open AccessDriving forces behind phase separation of the carboxy-terminal domain of RNA polymerase II
The condensation of RNA polymerase II (Pol II) into transcriptionally active clusters is critical for eukaryotic gene regulation and pre-mRNA transcription. Here the authors show that a tight network of tyrosine-proline interactions imparts temperature and concentration-dependent self-coacervation of Pol II’s C-terminal domain (CTD).
- David Flores-Solis
- , Irina P. Lushpinskaia
- & Markus Zweckstetter
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Article
| Open AccessStructural insights into the mechanism of GTP initiation of microtubule assembly
In this study the authors explore the enigma of GTP-triggered microtubule assembly. The proposed flexible model emphasizes longitudinal and lateral contacts, enhancing our understanding of microtubule nucleation and assembly.
- Ju Zhou
- , Anhui Wang
- & Hong-Wei Wang
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Article
| Open AccessCharacterization and structure-based protein engineering of a regiospecific saponin acetyltransferase from Astragalus membranaceus
Currently little is known about the acetylation on sugar moieties. Here the authors report a saponin acetyltransferase from Astragalus membranaceus, AmAT7-3, and utilise crystal structures and QM/MM computation to elucidate the catalytic mechanism: they generate mutants for specific site acetylation.
- Linlin Wang
- , Zhihui Jiang
- & Xue Qiao
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Article
| Open AccessAn inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism
GPR61 is an orphan GPCR of interest for treatment of appetite disorders, such as obesity and cachexia. Here, the authors report structures of GPR61 in its active and inactive states, including with a G protein-competitive small molecule inverse agonist.
- Joshua A. Lees
- , João M. Dias
- & Seungil Han
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Article
| Open AccessStructural basis of hydroxycarboxylic acid receptor signaling mechanisms through ligand binding
Hydroxy-carboxylic acid receptor (HCA) is an attractive drug target for neuroinflammation. Here, authors report cryo-EM structures of the HCA2 and HCA3-Gi complexes with multiple ligands, to describe the drug recognition and subtype selectivity.
- Shota Suzuki
- , Kotaro Tanaka
- & Yoshinori Fujiyoshi
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Article
| Open AccessAcetylation discriminates disease-specific tau deposition
The authors show that acetylation enhances the aggregation of 3R tau, while blocking the aggregation of 4R tau, providing a molecular basis for disease- and isoform-specific tau deposition.
- Pijush Chakraborty
- , Gwladys Rivière
- & Markus Zweckstetter
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Article
| Open AccessA conserved membrane protein negatively regulates Mce1 complexes in mycobacteria
Mycobacterial Mce systems are putative ABC transporters for lipids. Here, the authors revealed two distinct Mce1 complexes comprising different heterohexameric substrate binding assemblies that are negatively regulated via a novel mechanism.
- Yushu Chen
- , Yuchun Wang
- & Shu-Sin Chng
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Article
| Open AccessSpecific binding of GPR174 by endogenous lysophosphatidylserine leads to high constitutive Gs signaling
A number of orphan GPCRs show high constitutive activity. Here, the authors show that the high basal activity of some receptors can be explained by their sensitivity to naturally abundant lipids or by penetration of ECL2 in the orthosteric binding pocket.
- Yingying Nie
- , Zeming Qiu
- & Sanduo Zheng
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Article
| Open AccessSignal-noise metrics for RNA binding protein identification reveal broad spectrum protein-RNA interaction frequencies and dynamics
The identification of RNA-bound proteomes is hampered by a lack of quantitative metrics for evaluating RNA binding function. Here, the authors report LEAP-RBP as a method for purification of RNA-bound proteins and introduce signal-based metrics for robust profiling of RNA-bound proteomes.
- JohnCarlo Kristofich
- & Christopher V. Nicchitta
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Article
| Open AccessStructure of human drug transporters OATP1B1 and OATP1B3
A key step of drug metabolism in the human body is the uptake into liver cells, which is mediated by transport proteins of the OATP family. Here, authors report cryo-EM structures of two human OATP proteins, providing insight into their function.
- Anca-Denise Ciută
- , Kamil Nosol
- & Kaspar P. Locher
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Article
| Open AccessElevated concentrations cause upright alpha-synuclein conformation at lipid interfaces
The misfolding of alpha-synuclein is associated with neurodegenerative disorders such as Parkinson’s disease. The authors report a mechanism explaining why lipid membranes catalyze the formation of harmful aggregates at elevated concentrations.
- Steven J. Roeters
- , Kris Strunge
- & Tobias Weidner
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