2025
Molecular mechanism of Arp2/3 complex activation by nucleation-promoting factors and an actin monomer
Iyer S, Wu J, Pollard T, Voth G. Molecular mechanism of Arp2/3 complex activation by nucleation-promoting factors and an actin monomer. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2421467122. PMID: 40048273, PMCID: PMC11912402, DOI: 10.1073/pnas.2421467122.Peer-Reviewed Original ResearchConceptsArp2/3 complexActin monomersNeuronal Wiskott-Aldrich syndrome proteinWiskott-Aldrich syndrome proteinActin filament branchingMammalian Arp2/3 complexArp2/3 complex activationNucleation-promoting factorsActin-related proteinsCA motifsD-loopActin filamentsFilament branchingOrganelle movementBranch formationActive conformationActinMolecular mechanismsArp2/3Binding sitesArp3ProteinPathwayAtomistic molecular dynamics simulationsComplex activityDrugging Disordered Proteins by Conformational Selection to Inform Therapeutic Intervention
Bogin B, Levine Z. Drugging Disordered Proteins by Conformational Selection to Inform Therapeutic Intervention. Journal Of Chemical Theory And Computation 2025, 21: 3204-3215. PMID: 40029731, DOI: 10.1021/acs.jctc.4c01160.Peer-Reviewed Original ResearchConceptsIslet amyloid polypeptideIntrinsically disordered proteinsConformational selectionDisordered proteinsHuman islet amyloid polypeptideMolecular dynamics simulationsStable binding sitesSelf-assembling sequencesIAPP sequenceFixed conformationAmyloid polypeptideUmbrella samplingBinding preferencesConformational specificityTwo-state modelDynamics simulationsConformational heterogeneityNew conformationsBinding sitesMolecular binding mechanismsConformationBinding mechanismFoldamersStructural conformationProteinNorovirus co-opts NINJ1 for selective protein secretion
Song J, Zhang L, Moon S, Fang A, Wang G, Gheshm N, Loeb S, Cao P, Wallace J, Alfajaro M, Strine M, Beatty W, Jamieson A, Orchard R, Robinson B, Nice T, Wilen C, Orvedahl A, Reese T, Lee S. Norovirus co-opts NINJ1 for selective protein secretion. Science Advances 2025, 11: eadu7985. PMID: 40020060, PMCID: PMC11870086, DOI: 10.1126/sciadv.adu7985.Peer-Reviewed Original ResearchConceptsPlasma membrane ruptureDamage-associated molecular patternsNS1 secretionNinjurin-1Programmed cell deathAmino acid residuesViral replication sitesViral protein NS1CRISPR screensIntracellular viral proteinsMutagenesis studiesMembrane ruptureProtein NS1Unconventional pathwayCaspase-3Protein secretionViral proteinsReplication sitesCell deathMolecular patternsGenetic ablationNS1Pharmaceutical inhibitionDAMP releaseProteinHigh-resolution structures of Myosin-IC reveal a unique actin-binding orientation, ADP release pathway, and power stroke trajectory
Chavali S, Carman P, Shuman H, Ostap E, Sindelar C. High-resolution structures of Myosin-IC reveal a unique actin-binding orientation, ADP release pathway, and power stroke trajectory. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2415457122. PMID: 40014570, PMCID: PMC11892617, DOI: 10.1073/pnas.2415457122.Peer-Reviewed Original ResearchConceptsN-terminal extensionATP bindingRegulating ATP bindingADP releaseClass I myosinsLever arm swingStructure of myosinCryo-EM structureHigh-resolution structuresMembrane-bound vesiclesActin interfaceMyosin superfamilyMyosin familyActin filamentsAbsence of ADPMembrane remodelingNucleotide pocketMotile behaviorMyo1cPlasma membraneBiological functionsActinCryo-EM dataMotor domainMyosinTANGO2 is an acyl-CoA binding protein
Lujan A, Foresti O, Wojnacki J, Bigliani G, Brouwers N, Pena M, Androulaki S, Hashidate-Yoshida T, Kalyukina M, Novoselov S, Shindou H, Malhotra V. TANGO2 is an acyl-CoA binding protein. Journal Of Cell Biology 2025, 224: e202410001. PMID: 40015245, PMCID: PMC11867700, DOI: 10.1083/jcb.202410001.Peer-Reviewed Original ResearchConceptsAcyl-CoA binding proteinPeriphery of lipid dropletsAcyl-coenzyme A binding proteinA-binding proteinsAcyl-coenzyme AMitochondrial lumenHeme transportBinding proteinTANGO2Cellular localizationLipid dropletsStructural regionsLipid metabolismHeightened energy demandsMutationsProteinResiduesNrdEMetabolic crisisBindingMetabolismHemeSevere cardiomyopathyLipidT‑ALPHA: A Hierarchical Transformer-Based Deep Neural Network for Protein–Ligand Binding Affinity Prediction with Uncertainty-Aware Self-Learning for Protein-Specific Alignment
Kyro G, Smaldone A, Shee Y, Xu C, Batista V. T‑ALPHA: A Hierarchical Transformer-Based Deep Neural Network for Protein–Ligand Binding Affinity Prediction with Uncertainty-Aware Self-Learning for Protein-Specific Alignment. Journal Of Chemical Information And Modeling 2025, 65: 2395-2415. PMID: 39965912, DOI: 10.1021/acs.jcim.4c02332.Peer-Reviewed Original ResearchConceptsProtein-ligand binding affinity predictionBinding affinity predictionState-of-the-art performanceTransformer-based deep neural networksMultimodal feature representationAffinity predictionBinding affinity of small moleculesState-of-the-artDeep neural networksDeep learning modelsAffinity of small moleculesSelf-learning methodSARS-CoV-2 main proteasePredicted binding affinitiesFeature representationBinding affinityOn-target potencyNeural networkDrug discovery applicationsTransformation frameworkLearning modelsScoring functionCrystal structureSelf-learningMain proteaseStructural basis of promiscuous inhibition of Listeria virulence activator PrfA by oligopeptides
Hainzl T, Scortti M, Lindgren C, Grundström C, Krypotou E, Vázquez-Boland J, Sauer-Eriksson A. Structural basis of promiscuous inhibition of Listeria virulence activator PrfA by oligopeptides. Cell Reports 2025, 44: 115290. PMID: 39970044, DOI: 10.1016/j.celrep.2025.115290.Peer-Reviewed Original ResearchConceptsDNA-binding helix-turn-helix motifInhibit virulence gene expressionVirulence gene expressionPathogen Listeria monocytogenesPrfA activityVirulence factorsPrfAMaster regulatorsHydrophobic residuesInhibitory bindingGene expressionStructural basisBinding promiscuityPeptide bindingBinding sitesConformational changesPeptide residuesOligopeptidesPeptideInhibitory peptidesBindingPeptide backboneResiduesPromiscuous inhibitionExpressionG3BP1 ribonucleoprotein complexes regulate focal adhesion protein mobility and cell migration
Boraas L, Hu M, Martino P, Thornton L, Vejnar C, Zhen G, Zeng L, Parker D, Cox A, Giraldez A, Su X, Mayr C, Wang S, Nicoli S. G3BP1 ribonucleoprotein complexes regulate focal adhesion protein mobility and cell migration. Cell Reports 2025, 44: 115237. PMID: 39883578, PMCID: PMC11923778, DOI: 10.1016/j.celrep.2025.115237.Peer-Reviewed Original ResearchConceptsRNA-binding proteinsFocal adhesionsCell migrationStress granulesRNA-dependent mannerProtein mobilityFA proteinsRNA bindingDimerization domainSubcellular localizationRibonucleoprotein complexNon-stress conditionsFA sizeCell speedG3BP1RibonucleoproteinFA localizationBiological processesB-actinMRNAProteinCellsFA functionMigrationLocalizationStructural insights into HIV-2 CA lattice formation and FG-pocket binding revealed by single-particle cryo-EM
Cook M, Freniere C, Wu C, Lozano F, Xiong Y. Structural insights into HIV-2 CA lattice formation and FG-pocket binding revealed by single-particle cryo-EM. Cell Reports 2025, 44: 115245. PMID: 39864060, PMCID: PMC11912512, DOI: 10.1016/j.celrep.2025.115245.Peer-Reviewed Original ResearchConceptsHuman immunodeficiency virusHIV-2Features of human immunodeficiency virusHIV-2 CAHost factor interactionsImmunodeficiency virusHIV-1Human immunodeficiency virus capsidFunctionalized liposomesCapsid proteinHigh-resolution structuresSingle-particle cryo-EMCA assemblyCA hexamersFactor interactionsViral genomeCA latticeStructural basis for the interaction between the Drosophila RTK Sevenless (dROS1) and the GPCR BOSS
Zhang J, Tsutsui Y, Li H, Li T, Wang Y, Laraki S, Alarcon-Frias S, Stayrook S, Klein D. Structural basis for the interaction between the Drosophila RTK Sevenless (dROS1) and the GPCR BOSS. Nature Communications 2025, 16: 808. PMID: 39827240, PMCID: PMC11743138, DOI: 10.1038/s41467-025-55943-6.Peer-Reviewed Original ResearchConceptsFibronectin type IIIExtracellular regionReceptor tyrosine kinasesR7 photoreceptor cellsN-terminal domainCryo-EM structureC-terminal peptideDownstream signaling pathwaysDrosophila homologueBeta-strandsHelical hairpinHuman orthologHydrogen-deuterium exchange mass spectrometryMutagenesis studiesStructural basisRegulatory functionsSignaling pathwayTyrosine kinaseLigand bindingSevenlessComplex predictionBinding epitopeHDX-MSPhotoreceptor cellsBinding interactionsStructural basis for the transport and regulation mechanism of the multidrug resistance-associated protein 2
Koide E, Pietz H, Beltran J, Chen J. Structural basis for the transport and regulation mechanism of the multidrug resistance-associated protein 2. Nature Communications 2025, 16: 484. PMID: 39779684, PMCID: PMC11711199, DOI: 10.1038/s41467-024-55810-w.Peer-Reviewed Original ResearchConceptsAutoinhibited stateR domainPost-translocation stateSubstrate-binding sitePre-translocation stateATP-binding siteProtein 2Nucleotide-binding domain 2Cryogenic electron microscopyStructural basisDiverse array of compoundsDomain 2Cryo-EMRegulation mechanismChemotherapeutic resistanceConformational changesMultidrug resistanceArray of compoundsDiverse arrayConformational statesLiver homeostasisMultidrug resistance-associated protein 2Initial transportSubstrateCytosolSingle-molecule two- and three-colour FRET studies reveal a transition state in SNARE disassembly by NSF
Cheppali S, Li C, Xing W, Sun R, Yang M, Xue Y, Lu S, Yao J, Sun S, Chen C, Sui S. Single-molecule two- and three-colour FRET studies reveal a transition state in SNARE disassembly by NSF. Nature Communications 2025, 16: 250. PMID: 39747074, PMCID: PMC11695992, DOI: 10.1038/s41467-024-55531-0.Peer-Reviewed Original ResearchConceptsN-ethylmaleimide sensitive factorSNARE complexDisassembly of SNARE complexesStable four-helix bundleFour-helix bundleSNARE motifFluorescence spectroscopy approachesMinimal machineryAAA+ ATPasesProtein machineryAdapter proteinVesicle fusionMembrane fusionSyntaxinPhysiological processesSNAREProteinN-ethylmaleimideDisassemblySequential disassemblyMachinerySequential pathwayPathwayEukaryotesFusion
2024
Conformational response of αIIbβ3 and αVβ3 integrins to force
Kolasangiani R, Farzanian K, Chen Y, Schwartz M, Bidone T. Conformational response of αIIbβ3 and αVβ3 integrins to force. Structure 2024, 33: 289-299.e4. PMID: 39706199, DOI: 10.1016/j.str.2024.11.016.Peer-Reviewed Original ResearchConceptsBind similar ligandsExtended conformationAvb3 integrinCellular mechanosensingAdhesion receptorsSubunit domainsCell mechanosensingPlasma membraneIntegrinMechanical signalsAll-atom simulationsSingle molecule measurementsConformational responseSubunitMechanosensingStructural dynamicsSolid tissuesCellsMolecule measurementsConformationAvb3Circulating plateletsEquivalent levelMembraneIdentification of coilin interactors reveals coordinated control of Cajal body number and structure
Escayola D, Zhang C, Nischwitz E, Schärfen L, Dörner K, Straube K, Kutay U, Butter F, Neugebauer K. Identification of coilin interactors reveals coordinated control of Cajal body number and structure. Journal Of Cell Biology 2024, 224: e202305081. PMID: 39602297, PMCID: PMC11602656, DOI: 10.1083/jcb.202305081.Peer-Reviewed Original ResearchConceptsCajal bodiesSurvival motor neuron proteinCB assemblyModulating posttranslational modificationsRegulate RNA processingProtein interactorsProximity biotinylationRNA processingGenetic lociPosttranslational modificationsGene activationTranscription factorsFunctional screeningBiomolecular condensatesCoilinNeuronal proteinsCell nucleiProteinNuclear levelsNuclear positivityCB componentsCB numberBody numberAssemblyRibosomeStructures of complete extracellular assemblies of type I and type II Oncostatin M receptor complexes
Zhou Y, Stevis P, Cao J, Ehrlich G, Jones J, Rafique A, Sleeman M, Olson W, Franklin M. Structures of complete extracellular assemblies of type I and type II Oncostatin M receptor complexes. Nature Communications 2024, 15: 9776. PMID: 39532904, PMCID: PMC11557873, DOI: 10.1038/s41467-024-54124-1.Peer-Reviewed Original ResearchConceptsLeukemia inhibitory factor receptorOncostatin MExtracellular assemblyReceptor complexOSM receptorOncostatin M signalingOncostatin M receptorJuxtamembrane domainGp130 bindingCryogenic electron microscopyStructural basisGlycoprotein 130Cryo-EMFamily cytokinesBiological eventsGp130Therapeutic targetComplex formationFactor receptorType IMouse typesReceptorsAssemblyJuxtamembraneMutagenesisTranscription factor TCF1 binds to RORγt and orchestrates a regulatory network that determines homeostatic Th17 cell state
Mangani D, Subramanian A, Huang L, Cheng H, Krovi S, Wu Y, Yang D, Moreira T, Escobar G, Schnell A, Dixon K, Krishnan R, Singh V, Sobel R, Weiner H, Kuchroo V, Anderson A. Transcription factor TCF1 binds to RORγt and orchestrates a regulatory network that determines homeostatic Th17 cell state. Immunity 2024, 57: 2565-2582.e6. PMID: 39447575, PMCID: PMC11614491, DOI: 10.1016/j.immuni.2024.09.017.Peer-Reviewed Original ResearchConceptsCell statesRegulatory networksSpectrum of cell statesTh17 cellsTranscription factor TPro-inflammatory Th17 cellsHomeostatic tissue functionReceptor signalingMature T cellsAutoimmune tissue damageInterleukin (IL)-23Controlling tissue inflammationPro-inflammatory functionsPro-inflammatory cellsConditional deletionDevelopment of therapiesRestore homeostasisPro-inflammatory potentialTCF1T-helperT cellsRORgtTissue inflammationCellsInflammatory diseasesDNA-Based Molecular Clamp for Probing Protein Interactions and Structure under Force
Chung M, Zhou K, Powell J, Lin C, Schwartz M. DNA-Based Molecular Clamp for Probing Protein Interactions and Structure under Force. ACS Nano 2024, 18: 27590-27596. PMID: 39344156, PMCID: PMC11518680, DOI: 10.1021/acsnano.4c08663.Peer-Reviewed Original ResearchConceptsTalin rod domainNegative-stain electron microscopyDouble-stranded DNADNA clampProtein functionRod domainCryptic sitesProtein interactionsMolecular clampCellular mechanotransductionStudy proteinsBiochemical studiesCell biologyAdult physiologyProtein conformationTalinProteinBiochemical scaleMultiple diseasesDNAARPC5LVinculinStructural analysisEmbryogenesisDNA-based devicesVPS13B is localized at the interface between Golgi cisternae and is a functional partner of FAM177A1
Ugur B, Schueder F, Shin J, Hanna M, Wu Y, Leonzino M, Su M, McAdow A, Wilson C, Postlethwait J, Solnica-Krezel L, Bewersdorf J, De Camilli P. VPS13B is localized at the interface between Golgi cisternae and is a functional partner of FAM177A1. Journal Of Cell Biology 2024, 223: e202311189. PMID: 39331042, PMCID: PMC11451052, DOI: 10.1083/jcb.202311189.Peer-Reviewed Original ResearchConceptsLipid transportGolgi complex proteinGolgi subcompartmentsGolgi membranesGolgi cisternaeProtein familyFunctional partnersGolgi complexKO cellsComplex proteinsFAM177A1GolgiVPS13BAdjacent membranesMutationsProteinCohen syndromeLipidOrthologsInteractorsBrefeldinMembraneOrganellesSubcompartmentsDevelopmental disordersGAD65 tunes the functions of Best1 as a GABA receptor and a neurotransmitter conducting channel
Wang J, Owji A, Kittredge A, Clark Z, Zhang Y, Yang T. GAD65 tunes the functions of Best1 as a GABA receptor and a neurotransmitter conducting channel. Nature Communications 2024, 15: 8051. PMID: 39277606, PMCID: PMC11401937, DOI: 10.1038/s41467-024-52039-5.Peer-Reviewed Original ResearchConceptsCl- currentsRetinal pigment epithelial cellsIsoform of glutamic acid decarboxylasePigment epithelial cellsGlutamic acid decarboxylaseG-aminobutyric acidBestrophin-1BEST1GABA receptorsTransport metabolonEpithelial cellsGAD65Glutamate metabolizing enzymesAcid decarboxylaseGAD67Bestrophin channelsGABAExtracellular sitesNo effectAnion channelMetabolic enzymesPhysiological roleGlutamateCellsBestrophinHIV-1 usurps mixed-charge domain-dependent CPSF6 phase separation for higher-order capsid binding, nuclear entry and viral DNA integration
Jang S, Bedwell G, Singh S, Yu H, Arnarson B, Singh P, Radhakrishnan R, Douglas A, Ingram Z, Freniere C, Akkermans O, Sarafianos S, Ambrose Z, Xiong Y, Anekal P, Llopis P, KewalRamani V, Francis A, Engelman A. HIV-1 usurps mixed-charge domain-dependent CPSF6 phase separation for higher-order capsid binding, nuclear entry and viral DNA integration. Nucleic Acids Research 2024, 52: 11060-11082. PMID: 39258548, PMCID: PMC11472059, DOI: 10.1093/nar/gkae769.Peer-Reviewed Original ResearchConceptsHIV-1 infectionHIV-1Viral DNA integrationCPSF6 knockout cellsActivity in vitroHIV-1 pathogenesisHIV-1 integrationDNA integrityLiquid-liquid phase separationViral infectionNuclear specklesInfectionCapsids in vitroCPSF6NS depletionNuclear entryCapsid bindingCapsid-binding proteinKnockout cellsBinding proteinSR proteinsNuclear rimCo-aggregationDisordered regions
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