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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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Article
| Open AccessN-terminal α-amino SUMOylation of cofilin-1 is critical for its regulation of actin depolymerization
SUMOylation plays a key role in modulating protein function. Here, the authors uncover a form of SUMOylation, termed N-αSUMOylation, where SUMO1 attaches to the N-terminus of cofilin1. This SUMOylation promotes cofilin-1 binding to F-actin and cofilin-induced actin depolymerization.
- Weiji Weng
- , Xiaokun Gu
- & Yong Li
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Article
| Open AccessHigh-throughput screening of BAM inhibitors in native membrane environment
The bacterial insertase BAM is a key target for novel antibiotics that are urgently needed. Here, we describe the implementation of an assay that allows screening for BAM inhibitors in the native membrane in high-throughput format.
- Parthasarathi Rath
- , Adrian Hermann
- & Sebastian Hiller
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Article
| Open AccessDe novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8
Roy et al. describe a generalized method for computationally designing miniproteins selective for a single integrin heterodimer and conformational state. The designed αvβ6 inhibitor remains monomeric and maintains biological activity following aerosolization and shows excellent efficacy in bleomycin induced lung fibrosis.
- Anindya Roy
- , Lei Shi
- & David Baker
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Article
| Open AccessIdentification of motif-based interactions between SARS-CoV-2 protein domains and human peptide ligands pinpoint antiviral targets
In this work, the authors mapped putative interactions between protein domains encoded by the SARS-CoV-2 and intrinsically disordered regions of the human proteome. From the data, peptides with antiviral properties targeting Nsp9 and Nsp16 were identified.
- Filip Mihalič
- , Caroline Benz
- & Ylva Ivarsson
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Article
| Open AccessSHIELD: a platform for high-throughput screening of barrier-type DNA elements in human cells
Chromatin boundary elements are hard to define and characterize. Here the authors report Site-specific Heterochromatin Insertion of Elements at Lamina-associated Domains (SHIELD) for high-throughput screening of barrier-type DNA elements in human cells.
- Meng Zhang
- , Mary Elisabeth Ehmann
- & Huimin Zhao
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Article
| Open AccessMultidisciplinary studies with mutated HIV-1 capsid proteins reveal structural mechanisms of lattice stabilization
The effects of E45A or P38A capsid mutations on HIV core stability and infectivity are reversed by R132T or T216I. Here, authors used structural and biophysical methods to reveal short- and long-range rearrangements that explain stability changes.
- Anna T. Gres
- , Karen A. Kirby
- & Stefan G. Sarafianos
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Article
| Open AccessMethylene blue accelerates liquid-to-gel transition of tau condensates impacting tau function and pathology
Aberrant liquid-to-gel transition of biological condensates can lead to pathological fibrillization and disease. Here, the authors demonstrate that a small molecule, methylene blue, can decouple gelation from fibrillization of tau liquid droplets.
- Yongqi Huang
- , Jitao Wen
- & Meng Gao
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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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Article
| Open AccessMAVS integrates glucose metabolism and RIG-I-like receptor signaling
MAVS is an adapter protein involved in RIG-I-like receptor (RLR) signaling. Here, the authors show how MAVS link RLR-mediated signaling and glucose metabolism, employing distinct mechanisms in different organelles.
- Qiao-qiao He
- , Yu Huang
- & Shi Liu
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Article
| Open AccessElectrostatic interactions guide substrate recognition of the prokaryotic ubiquitin-like protein ligase PafA
Pupylation is the bacterial equivalent of ubiquitination. Here, the authors show selective binding of the Pup ligase PafA to substrates is driven by tertiary structure features rather than linear motifs and is achieved by a small number of electrostatic interactions, enabling quick adaption to new substrates.
- Matthias F. Block
- , Cyrille L. Delley
- & Eilika Weber-Ban
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Article
| Open AccessStructural basis for the allosteric modulation of rhodopsin by nanobody binding to its extracellular domain
G protein-coupled receptors (GPCRs) are involved in many physiological processes and are targets of intense drug discovery research. Here, the authors describe llama-derived nanobodies that allosterically modulate rhodopsin, a prototypical GPCR.
- Arum Wu
- , David Salom
- & Krzysztof Palczewski
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Article
| Open AccessTrim33 masks a non-transcriptional function of E2f4 in replication fork progression
Here the authors show that under replicative stress the E2f4 transcription factor recruits the Recql DNA helicase to facilitate DNA replication. The Trim33 ubiquitin ligase targets E2f4 to limit its interactions with Recql and chromatin.
- Vanessa Rousseau
- , Elias Einig
- & Nikita Popov
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Article
| Open AccessRedox driven B12-ligand switch drives CarH photoresponse
CarH is a bacterial B12-binding photoreceptor involved in transcriptional regulation. Here, the authors provide insights into B12 dynamics and associated cobalt redox changes following light activation. These demonstrate the CarH response integrates light and oxygen sensing.
- Harshwardhan Poddar
- , Ronald Rios-Santacruz
- & David Leys
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Article
| Open AccessThe net electrostatic potential and hydration of ABCG2 affect substrate transport
ABCG2, an ATP-binding cassette transporter, extrudes hundreds of hydrophilic and hydrophobic compounds from cells, playing roles in xenobiotic clearance or multidrug resistance in cancer. Gose et al provide key insights into ABCG2 substrate selection.
- Tomoka Gose
- , Heather M. Aitken
- & John D. Schuetz
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Article
| Open AccessLigand recognition and G protein coupling of the human itch receptor MRGPRX1
MRGPRX1 is a key GPCR expressed in the DRG for itch perception, generating scratch or avoidance behaviors. Here, authors provide structural and pharmacological insights into itch sensation, activation and G-protein signaling downstream of MRGPRX1.
- Lulu Guo
- , Yumu Zhang
- & Jin-Peng Sun
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Article
| Open AccessStructural basis for negative regulation of the Escherichia coli maltose system
MalY represses the E. coli maltose system by direct interaction with MalT that blocks its oligomerization. Maltotriose-binding leads to conformational remodelling of MalT and stabilizes the C-terminal domains required for downstream signalling.
- Yuang Wu
- , Yue Sun
- & Jijie Chai
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Article
| Open AccessMolecular insights into intrinsic transducer-coupling bias in the CXCR4-CXCR7 system
Chemokine receptors are G protein-coupled receptors (GPCRs) involved in immune responses and characterized by ligand promiscuity Here, the authors characterize signaling through chemokine receptors CXCR4 and CXCR7, with insights into intrinsic-bias encoded in the CXCR4-CXCR7 system.
- Parishmita Sarma
- , Carlo Marion C. Carino
- & Arun K. Shukla
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Article
| Open AccessA conserved membrane curvature-generating protein is crucial for autophagosome formation in fission yeast
Rop1 is the single representaive of a subfamily of the membrane-curvature generating REEPs in fission yeast. Wang et al. show that Rop1 is crucial for the macroautophagy of organelles and cytosolic proteins, facilitating autophagosome formation.
- Ning Wang
- , Yoko Shibata
- & Tom A. Rapoport
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Article
| Open AccessMolecular basis of Mg2+ permeation through the human mitochondrial Mrs2 channel
Mrs2 is a mitochondrial Mg2+ channel that is essential for metabolic function. Here, the authors present cryo-EM structures of human Mrs2 revealing symmetrical pentameric assembly and how Mrs2 permeates Mg2+.
- Ming Li
- , Yang Li
- & Yuequan Shen
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Article
| Open AccessBtuB TonB-dependent transporters and BtuG surface lipoproteins form stable complexes for vitamin B12 uptake in gut Bacteroides
Uptake of vitamin B12 is important for colonisation of the gut by Bacteroides species. Here the authors characterise B12 uptake in Bacteroides thetaiotaomicron, mediated by outer membrane protein complexes consisting of surface-exposed BtuG lipoproteins and BtuB TonB-dependent transporters.
- Javier Abellon-Ruiz
- , Kalyanashis Jana
- & Bert van den Berg
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Article
| Open AccessControl of motor landing and processivity by the CAP-Gly domain in the KIF13B tail
Intracellular transport of material along microtubules by kinesin motors is critical for cellular homeostasis. Here the authors uncover a unique role for a specialized kinesin tail domain in directing motor transport along specific microtubule tracks.
- Xiangyu Fan
- & Richard J. McKenney
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Article
| Open AccessMembrane mediated mechanical stimuli produces distinct active-like states in the AT1 receptor
The AT1 GPCR plays an essential role in cardiovascular regulation and may be activated by the peptide AngII as well as membrane stretch. Here, Poudel et al. use molecular simulations to show that membrane-mediated activation produces distinct active-like conformations when compared to activation by AngII.
- Bharat Poudel
- , Rajitha Rajeshwar T
- & Juan M. Vanegas
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Article
| Open AccessThe AT-hook is an evolutionarily conserved auto-regulatory domain of SWI/SNF required for cell lineage priming
This study demonstrates that an evolutionary conserved, autoregulatory ‘AT-hook’ domain of SWI/SNF regulates gene transcription and enhancer activation by modulating SWI/SNF intrinsic catalytic activity and is critical for cell lineage priming.
- Dhurjhoti Saha
- , Solomon Hailu
- & Blaine Bartholomew
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Article
| Open AccessThe Ycf48 accessory factor occupies the site of the oxygen-evolving manganese cluster during photosystem II biogenesis
The Ycf48 accessory factor is important for the assembly and repair of the photosystem II (PSII) complex of oxygenic photosynthesis. Here, the authors show that Ycf48 occupies the binding site of the oxygen evolving Mn cluster early in PSII biogenesis.
- Ziyu Zhao
- , Irene Vercellino
- & Josef Komenda
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Article
| Open AccessEnergetic robustness to large scale structural fluctuations in a photosynthetic supercomplex
Robust photosynthetic light harvesting occurs in large membrane supercomplexes. Here, the authors show that supercomplexes occupy an unexpectedly large range of conformations yet maintain their efficiency due to specific, critical chlorophylls.
- Dvir Harris
- , Hila Toporik
- & Yuval Mazor
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Article
| Open AccessPartition complex structure can arise from sliding and bridging of ParB dimers
In many bacteria and plasmids, DNA segregation is controlled by the ParABS system, an essential component of which is the formation of a nucleoprotein complex. Here, making use of recent discoveries, the authors develop a sliding and bridging model to predict the fine structure of this complex.
- Lara Connolley
- , Lucas Schnabel
- & Seán M. Murray
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