{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T12:23:42Z","timestamp":1787228622749,"version":"build-2736575974"},"reference-count":82,"publisher":"American Chemical Society (ACS)","issue":"33","license":[{"start":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T00:00:00Z","timestamp":1786147200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T00:00:00Z","timestamp":1786147200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T00:00:00Z","timestamp":1786147200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM147333"],"award-info":[{"award-number":["R35GM147333"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\u03b1-Synuclein (\u03b1Syn) remodels cellular membranes through interactions that involve both its structured, membrane-binding N-terminal domain (NTD) and intrinsically disordered C-terminal domain (CTD). While the amphipathic NTD helix is known to insert into lipid bilayers and generate curvature, the contribution of the acidic CTD remains unclear. Here, we dissect the individual and complementary roles of these domains using Supported Bilayers with Excess Membrane Reservoir (SUPER) templates to quantify membrane remodeling via membrane fission and membrane morphological deformations (i.e., membrane budding and tubulation). We show that both the NTD and CTD independently remodel membranes, while full-length \u03b1Syn exhibits greater remodeling ability than either the NTD or CTD in isolation. This result demonstrates an additive effect between helix insertion of the NTD and the tethered, disordered CTD. To further probe the mechanism of membrane remodeling by the CTD, we modulated the chain length of the protein, the bulk ionic strength of the solution (i.e., charge screening), and applied relevant polymer scaling laws for disordered proteins. Our results suggest that the membrane remodeling mechanism for the disordered CTD is electrostatic in nature, stemming from protein\u2013protein repulsion at elevated binding densities. Together, our findings reveal a complementary energetic mechanism in which N-terminal helix insertion biases membrane curvature and the disordered, C-terminal domain adds an additional electrostatic component that helps to overcome the free energy barrier for membrane bending.<\/jats:p>","DOI":"10.1021\/acs.jpcb.6c01863","type":"journal-article","created":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T15:02:38Z","timestamp":1786201358000},"page":"8349-8362","source":"Crossref","is-referenced-by-count":0,"title":["Membrane Remodeling by \u03b1-Synuclein Emerges\nfrom Complementary Contributions of Its Structured and Disordered\nDomains"],"prefix":"10.1021","volume":"130","author":[{"given":"David H.","family":"Johnson","sequence":"first","affiliation":[{"name":"University of Southern California , , , ,","place":["Los Angeles, California, United States, 90089"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia Shiuan","family":"Liow","sequence":"additional","affiliation":[{"name":"University of Southern California , , , ,","place":["Los Angeles, California, United States, 90089"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orianna H.","family":"Kou","sequence":"additional","affiliation":[{"name":"University of Southern California , , , ,","place":["Los Angeles, California, United States, 90089"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2341-8923","authenticated-orcid":true,"given":"Wade F.","family":"Zeno","sequence":"additional","affiliation":[{"name":"University of Southern California , , , ,","place":["Los Angeles, California, United States, 90089"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,8]]},"reference":[{"issue":"8","key":"2026082007202105300_cit1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.08-08-02804.1988","article-title":"Synuclein: a neuron-specific protein\nlocalized to the nucleus and presynaptic nerve terminal","volume":"8","author":"Maroteaux","year":"1988","journal-title":"J. Neurosci."},{"issue":"8","key":"2026082007202105300_cit2","doi-asserted-by":"publisher","first-page":"1287","DOI":"10.1038\/s41556-024-01456-1","article-title":"VAMP2 chaperones \u03b1-synuclein in synaptic vesicle\nco-condensates","volume":"26","author":"Wang","year":"2024","journal-title":"Nat. Cell Biol."},{"issue":"44","key":"2026082007202105300_cit3","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2310174120","article-title":"Neutral lysophosphatidylcholine mediates\n\u03b1-synuclein-induced synaptic vesicle clustering","volume":"120","author":"Lai","year":"2023","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"issue":"2","key":"2026082007202105300_cit4","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/j.tins.2022.11.007","article-title":"\u03b1-Synuclein in synaptic function\nand dysfunction","volume":"46","author":"Sharma","year":"2023","journal-title":"Trends Neurosci."},{"issue":"1","key":"2026082007202105300_cit5","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2022.167714","article-title":"Functional and Pathological Effects of \u03b1-Synuclein\non Synaptic SNARE Complexes","volume":"435","author":"Gao","year":"2023","journal-title":"J. Mol. Biol."},{"key":"2026082007202105300_cit6","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1002\/mds.10559","article-title":"Clinical overview of the synucleinopathies","volume":"18","author":"Marti\u0301","year":"2003","journal-title":"Mov. Disord."},{"issue":"6","key":"2026082007202105300_cit7","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24065914","article-title":"Alpha Synuclein: Neurodegeneration\nand Inflammation","volume":"24","author":"Forloni","year":"2023","journal-title":"Int. J. Mol. Sci."},{"issue":"8","key":"2026082007202105300_cit8","doi-asserted-by":"publisher","first-page":"3815","DOI":"10.1021\/acschemneuro.9b00320","article-title":"Cardiolipin Promotes Pore-Forming\nActivity of Alpha-Synuclein Oligomers in Mitochondrial Membranes","volume":"10","author":"Ghio","year":"2019","journal-title":"ACS Chem. Neurosci."},{"issue":"23","key":"2026082007202105300_cit9","doi-asserted-by":"publisher","first-page":"20710","DOI":"10.1074\/jbc.M110.213538","article-title":"Direct Membrane\nAssociation Drives Mitochondrial Fission by the Parkinson Disease-associated\nProtein \u03b1-Synuclein*","volume":"286","author":"Nakamura","year":"2011","journal-title":"J. Biol. Chem."},{"issue":"35","key":"2026082007202105300_cit10","doi-asserted-by":"publisher","first-page":"29301","DOI":"10.1074\/jbc.M112.365817","article-title":"Remodeling of Lipid Vesicles into\nCylindrical Micelles by \u03b1-Synuclein in an Extended \u03b1-Helical\nConformation*","volume":"287","author":"Mizuno","year":"2012","journal-title":"J. Biol. Chem."},{"issue":"42","key":"2026082007202105300_cit11","doi-asserted-by":"publisher","first-page":"32486","DOI":"10.1074\/jbc.M110.139576","article-title":"Membrane Curvature\nInduction and Tubulation Are Common Features of Synucleins and Apolipoproteins","volume":"285","author":"Varkey","year":"2010","journal-title":"J. Biol. Chem."},{"issue":"PB","key":"2026082007202105300_cit12","doi-asserted-by":"publisher","first-page":"1594","DOI":"10.1016\/j.bbamem.2016.03.012","article-title":"Membrane remodeling and mechanics:\nExperiments and simulations of \u03b1-Synuclein","volume":"1858","author":"West","year":"2016","journal-title":"Biochim. Biophys. Acta (BBA) - Biomemb."},{"issue":"6","key":"2026082007202105300_cit13","doi-asserted-by":"publisher","first-page":"1582","DOI":"10.1021\/acs.jpcb.0c09192","article-title":"Membrane Remodeling\nand Stimulation of Aggregation Following \u03b1-Synuclein Adsorption\nto Phosphotidylserine Vesicles","volume":"125","author":"Hoover","year":"2021","journal-title":"J. Phys. Chem.\nB"},{"issue":"43","key":"2026082007202105300_cit14","doi-asserted-by":"publisher","first-page":"15970","DOI":"10.1021\/ja405993r","article-title":"Membrane Remodeling\nby \u03b1-Synuclein and Effects on Amyloid Formation","volume":"135","author":"Jiang","year":"2013","journal-title":"J. Am. Chem. Soc."},{"issue":"25","key":"2026082007202105300_cit15","doi-asserted-by":"publisher","first-page":"14178","DOI":"10.1073\/pnas.1914670117","article-title":"Single-vesicle\nimaging reveals lipid-selective and stepwise membrane disruption by\nmonomeric \u03b1-synuclein","volume":"117","author":"Hannestad","year":"2020","journal-title":"Proc. Natl. Acad.\nSci. U.S.A."},{"issue":"19","key":"2026082007202105300_cit16","doi-asserted-by":"publisher","first-page":"5886","DOI":"10.1021\/jp1121917","article-title":"\u03b1-Synuclein-induced\ntubule formation in lipid bilayers","volume":"115","author":"Pandey","year":"2011","journal-title":"J. Phys.\nChem. B"},{"issue":"29","key":"2026082007202105300_cit17","doi-asserted-by":"publisher","first-page":"20883","DOI":"10.1074\/jbc.M113.478297","article-title":"\u03b1-Synuclein\nSenses Lipid Packing Defects and Induces Lateral Expansion of Lipids\nLeading to Membrane Remodeling","volume":"288","author":"Ouberai","year":"2013","journal-title":"J. Biol. Chem."},{"issue":"2","key":"2026082007202105300_cit18","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1007\/s00232-017-9946-1","article-title":"\u03b1-Synuclein\u2019s\nUniquely Long Amphipathic Helix Enhances its Membrane Binding and\nRemodeling Capacity","volume":"250","author":"Braun","year":"2017","journal-title":"J. Membr. Biol."},{"issue":"28","key":"2026082007202105300_cit19","doi-asserted-by":"publisher","first-page":"9962","DOI":"10.1021\/ja5016958","article-title":"\u03b1-Synuclein-Induced\nMembrane Remodeling Is Driven by Binding Affinity, Partition Depth,\nand Interleaflet Order Asymmetry","volume":"136","author":"Braun","year":"2014","journal-title":"J. Am. Chem.\nSoc."},{"key":"2026082007202105300_cit20","doi-asserted-by":"crossref","unstructured":"Birol, M.; Mun\u0303oz, I. I. D.; Rhoades, E.\n          The C-terminus\nof \u03b1-Synuclein Regulates its Dynamic Cellular Internalization\nby Neurexin 1\u03b2\n          Mol. Biol. Cell\n          2023; Vol. 34(13), 10.1091\/mbc.E22-11-0496.","DOI":"10.1091\/mbc.E22-11-0496"},{"issue":"11","key":"2026082007202105300_cit21","doi-asserted-by":"publisher","first-page":"2049","DOI":"10.1021\/acschemneuro.3c00040","article-title":"Intrinsic Disorder in \u03b1-Synuclein\nRegulates the Exocytotic Fusion Pore Transition","volume":"14","author":"Di Bartolo","year":"2023","journal-title":"ACS Chem. Neurosci."},{"issue":"16","key":"2026082007202105300_cit22","doi-asserted-by":"publisher","first-page":"2293","DOI":"10.1016\/j.jmb.2018.03.024","article-title":"Structure\nVersus Stochasticity\u2500The Role of Molecular Crowding and Intrinsic\nDisorder in Membrane Fission","volume":"430","author":"Snead","year":"2018","journal-title":"J. Mol. Biol."},{"issue":"1","key":"2026082007202105300_cit23","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms8875","article-title":"Intrinsically disordered proteins drive membrane curvature","volume":"6","author":"Busch","year":"2015","journal-title":"Nat. Commun."},{"issue":"5","key":"2026082007202105300_cit24","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1016\/j.tibs.2024.02.005","article-title":"Protein\u2013membrane\ninteractions: sensing and generating curvature","volume":"49","author":"Johnson","year":"2024","journal-title":"Trends Biochem. Sci."},{"issue":"43","key":"2026082007202105300_cit25","doi-asserted-by":"publisher","first-page":"8706","DOI":"10.1039\/C9SM01495K","article-title":"Structured and intrinsically disordered domains within\nAmphiphysin1 work together to sense and drive membrane curvature","volume":"15","author":"Zeno","year":"2019","journal-title":"Soft Matter"},{"issue":"10","key":"2026082007202105300_cit26","doi-asserted-by":"publisher","first-page":"8209","DOI":"10.1074\/jbc.M111587200","article-title":"Unusual structural organization of\nthe endocytic proteins AP180 and epsin 1","volume":"277","author":"Kalthoff","year":"2002","journal-title":"J.\nBiol. Chem."},{"issue":"5","key":"2026082007202105300_cit27","doi-asserted-by":"publisher","first-page":"2360","DOI":"10.1016\/S0006-3495(02)75581-1","article-title":"Relating\ninteractions between neurofilaments to the structure of axonal neurofilament\ndistributions through polymer brush models","volume":"82","author":"Kumar","year":"2002","journal-title":"Biophys. J."},{"issue":"16","key":"2026082007202105300_cit28","doi-asserted-by":"publisher","first-page":"E3258","DOI":"10.1073\/pnas.1616199114","article-title":"Membrane\nfission by protein crowding","volume":"114","author":"Snead","year":"2017","journal-title":"Proc. Natl. Acad.\nSci. U.S.A."},{"issue":"2","key":"2026082007202105300_cit29","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1083\/jcb.201807119","article-title":"BAR scaffolds\ndrive membrane fission by crowding disordered domains","volume":"218","author":"Snead","year":"2019","journal-title":"J. Cell Biol."},{"issue":"16","key":"2026082007202105300_cit30","doi-asserted-by":"publisher","first-page":"3241","DOI":"10.1039\/C4SM02856B","article-title":"Designing lipids for selective partitioning into liquid\nordered membrane domains","volume":"11","author":"Momin","year":"2015","journal-title":"Soft Matter"},{"issue":"12","key":"2026082007202105300_cit31","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0015801","article-title":"Targeted Amino-Terminal Acetylation of Recombinant\nProteins in E. coli","volume":"5","author":"Johnson","year":"2010","journal-title":"PLoS One"},{"issue":"1","key":"2026082007202105300_cit32","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-025-08622-7","article-title":"Lipid packing\ndefects are necessary and sufficient for membrane binding of \u03b1-synuclein","volume":"8","author":"Johnson","year":"2025","journal-title":"Commun. Biol."},{"issue":"1","key":"2026082007202105300_cit33","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1038\/nprot.2012.152","article-title":"Analyzing membrane remodeling and\nfission using supported bilayers with excess membrane reservoir","volume":"8","author":"Neumann","year":"2013","journal-title":"Nat. Protoc."},{"issue":"1","key":"2026082007202105300_cit34","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-06532-3","article-title":"Synergy\nbetween intrinsically disordered domains and structured proteins amplifies\nmembrane curvature sensing","volume":"9","author":"Zeno","year":"2018","journal-title":"Nat. Commun."},{"issue":"26","key":"2026082007202105300_cit35","doi-asserted-by":"publisher","first-page":"10361","DOI":"10.1021\/jacs.9b03927","article-title":"Molecular\nMechanisms of Membrane Curvature Sensing by a Disordered Protein","volume":"141","author":"Zeno","year":"2019","journal-title":"J. Am. Chem. Soc."},{"issue":"3","key":"2026082007202105300_cit36","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1016\/j.devcel.2013.06.019","article-title":"Advances in Analysis\nof Low Signal-to-Noise Images Link Dynamin and AP2 to the Functions\nof an Endocytic Checkpoint","volume":"26","author":"Aguet","year":"2013","journal-title":"Dev. Cell"},{"key":"2026082007202105300_cit37","unstructured":"Johnson, D. H. Z.\n          \n          Wade, SUPER\nTemplate Remodeling Images. 202610.5281\/zenodo.20615905."},{"issue":"11","key":"2026082007202105300_cit38","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1038\/nchembio.213","article-title":"How curved membranes recruit amphipathic helices and\nprotein anchoring motifs","volume":"5","author":"Hatzakis","year":"2009","journal-title":"Nat. Chem. Biol."},{"issue":"2","key":"2026082007202105300_cit39","doi-asserted-by":"publisher","first-page":"917","DOI":"10.1016\/S0006-3495(98)77580-0","article-title":"Structure and Interactions of Fully\nHydrated Dioleoylphosphatidylcholine Bilayers","volume":"75","author":"Tristram-Nagle","year":"1998","journal-title":"Biophys. J."},{"issue":"12","key":"2026082007202105300_cit40","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrp.2024.102309","article-title":"Tipping point in \u03b1-synuclein-membrane interactions from stable\nprotein-covered vesicles to amyloid aggregation","volume":"5","author":"Makasewicz","year":"2024","journal-title":"Cell Rep. Phys. Sci."},{"issue":"1","key":"2026082007202105300_cit41","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-39843-1","article-title":"Elevated concentrations cause upright alpha-synuclein\nconformation at lipid interfaces","volume":"14","author":"Roeters","year":"2023","journal-title":"Nat. Commun."},{"issue":"1","key":"2026082007202105300_cit42","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4827","article-title":"Direct observation of the three regions\nin \u03b1-synuclein that determine its membrane-bound behaviour","volume":"5","author":"Fusco","year":"2014","journal-title":"Nat. Commun."},{"issue":"4","key":"2026082007202105300_cit43","doi-asserted-by":"publisher","DOI":"10.1002\/pro.70067","article-title":"Sizes, conformational\nfluctuations, and SAXS profiles for intrinsically disordered proteins","volume":"34","author":"Mugnai","year":"2025","journal-title":"Protein Sci."},{"issue":"4","key":"2026082007202105300_cit44","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1051\/jphys:01975003604028100","article-title":"The Lagrangian\ntheory of polymer solutions at intermediate concentrations","volume":"36","author":"des Cloizeaux","year":"1975","journal-title":"J. Phys."},{"key":"2026082007202105300_cit45","volume-title":"Scaling Concepts in Polymer Physics","author":"De Gennes","year":"1979"},{"issue":"18","key":"2026082007202105300_cit46","doi-asserted-by":"publisher","first-page":"3320","DOI":"10.1016\/j.bpj.2022.08.028","article-title":"Molecular mechanisms of steric pressure generation\nand membrane remodeling by disordered proteins","volume":"121","author":"Houser","year":"2022","journal-title":"Biophys. J."},{"issue":"20","key":"2026082007202105300_cit47","doi-asserted-by":"publisher","first-page":"8157","DOI":"10.1073\/pnas.0901931106","article-title":"Proteomics analyses\nreveal the evolutionary conservation and divergence of N-terminal\nacetyltransferases from yeast and humans","volume":"106","author":"Arnesen","year":"2009","journal-title":"Proc.\nNatl. Acad. Sci. U.S.A."},{"issue":"7453","key":"2026082007202105300_cit48","doi-asserted-by":"publisher","first-page":"E4","DOI":"10.1038\/nature12125","article-title":"Properties\nof native brain \u03b1-synuclein","volume":"498","author":"Burre\u0301","year":"2013","journal-title":"Nature"},{"issue":"19","key":"2026082007202105300_cit49","doi-asserted-by":"publisher","first-page":"15345","DOI":"10.1074\/jbc.M111.318949","article-title":"\u03b1-Synuclein\nin Central Nervous System and from Erythrocytes, Mammalian Cells,\nand Escherichia coli Exists Predominantly\nas Disordered Monomer","volume":"287","author":"Fauvet","year":"2012","journal-title":"J. Biol. Chem."},{"issue":"8","key":"2026082007202105300_cit50","doi-asserted-by":"publisher","first-page":"4145","DOI":"10.1021\/la703788h","article-title":"Kinetic\nControl of Histidine-Tagged Protein Surface Density on Supported Lipid\nBilayers","volume":"24","author":"Nye","year":"2008","journal-title":"Langmuir"},{"issue":"34","key":"2026082007202105300_cit51","doi-asserted-by":"publisher","first-page":"6372","DOI":"10.1039\/D2SM00915C","article-title":"Binding of His-tagged\nfluorophores to lipid bilayers of giant vesicles","volume":"18","author":"Pramanik","year":"2022","journal-title":"Soft Matter"},{"issue":"7","key":"2026082007202105300_cit52","doi-asserted-by":"publisher","first-page":"2279","DOI":"10.1016\/j.bpj.2010.07.056","article-title":"Effects of curvature and composition on \u03b1-synuclein\nbinding to lipid vesicles","volume":"99","author":"Middleton","year":"2010","journal-title":"Biophys. J."},{"key":"2026082007202105300_cit53","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2021.108966","article-title":"An overview of the synaptic vesicle\nlipid composition","volume":"709","author":"Binotti","year":"2021","journal-title":"Arch. Biochem. Biophys."},{"issue":"1","key":"2026082007202105300_cit54","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-48734-y","article-title":"Lipidome atlas of the adult human brain","volume":"15","author":"Osetrova","year":"2024","journal-title":"Nat. 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Adv."},{"issue":"6187","key":"2026082007202105300_cit58","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1126\/science.1252884","article-title":"Composition\nof isolated synaptic boutons reveals the amounts of vesicle trafficking\nproteins","volume":"344","author":"Wilhelm","year":"2014","journal-title":"Science"},{"issue":"2","key":"2026082007202105300_cit59","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1016\/0896-6273(95)90302-x","article-title":"The precursor\nprotein of non-A beta component of Alzheimer\u2019s disease amyloid\nis a presynaptic protein of the central nervous system","volume":"14","author":"Iwai","year":"1995","journal-title":"Neuron"},{"issue":"9","key":"2026082007202105300_cit60","doi-asserted-by":"publisher","first-page":"E1206","DOI":"10.1073\/pnas.1524128113","article-title":"Kinetic model of the aggregation of alpha-synuclein\nprovides insights into prion-like spreading","volume":"113","author":"Iljina","year":"2016","journal-title":"Proc. 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