{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T04:13:41Z","timestamp":1788149621165,"version":"build-2803163510"},"reference-count":92,"publisher":"American Chemical Society (ACS)","issue":"8","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["12374208"],"award-info":[{"award-number":["12374208"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22477132"],"award-info":[{"award-number":["22477132"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32371281"],"award-info":[{"award-number":["32371281"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2022M720815"],"award-info":[{"award-number":["2022M720815"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005089","name":"Natural Science Foundation of Beijing Municipality","doi-asserted-by":"publisher","award":["5254039"],"award-info":[{"award-number":["5254039"]}],"id":[{"id":"10.13039\/501100005089","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFF1204402"],"award-info":[{"award-number":["2023YFF1204402"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014973","name":"National Laboratory of Biomacromolecules","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100014973","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The Parkinson\u2019s disease-related protein \u03b1-synuclein can form solid amyloid fibrils through liquid\u2013liquid phase separation (LLPS) and liquid-to-solid phase transition. The most deleterious familial mutation E46K has recently been shown to enhance \u03b1-synuclein LLPS and subsequent solidification; yet, the precise mechanisms remain largely unknown. Here, using molecular dynamics simulations at different spatiotemporal scales combined with biochemical experiments, we show that the E46K mutation acts as an electrostatic switch to remodel interactions between the oppositely charged N-terminal domain (NTD) and C-terminal domain (CTD) of \u03b1-synuclein. This remodeling shifts the interaction site of NTD with CTD from its N-terminus to the mutation region. Such reorganization increases the hydrophobic solvent exposure of key LLPS-promoting motifs, potentially facilitating intermolecular interactions that initiate phase separation. Phase coexistence simulations further support this hypothesis, showing that the E46K mutant exhibits enhanced LLPS and solidification propensities. This enhancement is primarily driven by intermolecular electrostatic interactions between the mutation region and the CTD, followed by the hydrophobic NAC\u2013NAC interactions mediated by the LLPS-promoting motifs. Collectively, these results reveal that NTD\u2013CTD electrostatic crosstalk acts as the key modulator of \u03b1-synuclein phase separation, while NAC\u2013NAC interactions play an auxiliary role, both of which synergistically govern \u03b1-synuclein phase separation. This study offers a complete and detailed mechanistic framework for understanding \u03b1-synuclein phase separation and its enhancement induced by the E46K mutation.<\/jats:p>","DOI":"10.1021\/jacsau.6c00631","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T17:01:57Z","timestamp":1786554117000},"page":"4537-4549","source":"Crossref","is-referenced-by-count":0,"title":["Pathological Mutation\nE46K Acts as an Electrostatic\nSwitch to Increase Distant Interdomain Interactions and Promote \u03b1-Synuclein\nPhase Separation"],"prefix":"10.1021","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1686-6979","authenticated-orcid":true,"given":"Zhongyuan","family":"Yang","sequence":"first","affiliation":[{"name":"Fudan University , , 2005 Songhu Road, Yangpu District , ,","place":["Shanghai, China, 200438"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2976-5547","authenticated-orcid":true,"given":"Yiming","family":"Tang","sequence":"additional","affiliation":[{"name":"Fudan University , , 2005 Songhu Road, Yangpu District , ,","place":["Shanghai, China, 200438"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jitao","family":"Wen","sequence":"additional","affiliation":[{"name":"Institute of Biophysics, Chinese Academy of Sciences , , 15 Datun Road, Chaoyang District , ,","place":["Beijing, China, 100101"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8655-0780","authenticated-orcid":true,"given":"Cong","family":"Guo","sequence":"additional","affiliation":[{"name":"Shanghai University , , 99 Shangda Rd, Baoshan District , ,","place":["Shanghai, China, 200444"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6093-8119","authenticated-orcid":true,"given":"Yun","family":"Zhou","sequence":"additional","affiliation":[{"name":"Fudan University , , 2005 Songhu Road, Yangpu District , ,","place":["Shanghai, China, 200438"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihan","family":"Wang","sequence":"additional","affiliation":[{"name":"Fudan University , , 2005 Songhu Road, Yangpu District , ,","place":["Shanghai, China, 200438"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Pan","sequence":"additional","affiliation":[{"name":"Fudan University , , 2005 Songhu Road, Yangpu District , ,","place":["Shanghai, China, 200438"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Tan","sequence":"additional","affiliation":[{"name":"Fudan University , , 2005 Songhu Road, Yangpu District , ,","place":["Shanghai, China, 200438"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0137-0997","authenticated-orcid":true,"given":"Sarah","family":"Perrett","sequence":"additional","affiliation":[{"name":"Institute of Biophysics, Chinese Academy of Sciences , , 15 Datun Road, Chaoyang District , ,","place":["Beijing, China, 100101"]},{"name":"University of Cambridge , , Lensfield Road , ,","place":["Cambridge, U.K., CB2 1EW"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7743-8236","authenticated-orcid":true,"given":"Si","family":"Wu","sequence":"additional","affiliation":[{"name":"Institute of Biophysics, Chinese Academy of Sciences , , 15 Datun Road, Chaoyang District , ,","place":["Beijing, China, 100101"]},{"name":"University of the Chinese Academy of Sciences , 19A Yuquan Road, Shijingshan District , ,","place":["Beijing, China, 100049"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5814-3328","authenticated-orcid":true,"given":"Guanghong","family":"Wei","sequence":"additional","affiliation":[{"name":"Fudan University , , 2005 Songhu Road, Yangpu District , ,","place":["Shanghai, China, 200438"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"issue":"8036","key":"2026083023172351500_cit1","doi-asserted-by":"publisher","first-page":"1204","DOI":"10.1038\/s41586-024-07990-0","article-title":"Biomolecular condensates mediate bending and scission of endosome\nmembranes","volume":"634","author":"Wang","year":"2024","journal-title":"Nature"},{"issue":"9","key":"2026083023172351500_cit2","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1038\/s41580-024-00739-7","article-title":"Splicing regulation\nthrough biomolecular condensates and membraneless\norganelles","volume":"25","author":"Giudice","year":"2024","journal-title":"Nat. Rev. Mol. Cell Biol."},{"issue":"3","key":"2026083023172351500_cit3","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1038\/s41580-024-00789-x","article-title":"Transcription regulation\nby biomolecular condensates","volume":"26","author":"Pei","year":"2025","journal-title":"Nat. Rev. Mol.\nCell Biol."},{"issue":"6777","key":"2026083023172351500_cit4","doi-asserted-by":"publisher","DOI":"10.1126\/science.adv6588","article-title":"Multiscale\nstructure\nof chromatin condensates explains phase separation and material properties","volume":"390","author":"Zhou","year":"2025","journal-title":"Science"},{"issue":"7","key":"2026083023172351500_cit5","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1038\/s44286-025-00242-6","article-title":"Biomolecular\ncondensates as regulators of enzymatic reactions","volume":"2","author":"Papp","year":"2025","journal-title":"Nat. Chem. 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Biol. Chem."},{"issue":"8","key":"2026083023172351500_cit15","doi-asserted-by":"publisher","first-page":"2804","DOI":"10.1523\/JNEUROSCI.08-08-02804.1988","article-title":"Synuclein: a neuron-specific\nprotein\nlocalized to the nucleus and presynaptic nerve terminal","volume":"8","author":"Maroteaux","year":"1988","journal-title":"J. Neurosci."},{"issue":"10291","key":"2026083023172351500_cit16","doi-asserted-by":"publisher","first-page":"2284","DOI":"10.1016\/S0140-6736(21)00218-X","article-title":"Parkinson\u2019s\ndisease","volume":"397","author":"Bloem","year":"2021","journal-title":"Lancet"},{"issue":"9","key":"2026083023172351500_cit17","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1021\/ar050073t","article-title":"The aggregation\nand fibrillation of \u03b1-synuclein","volume":"39","author":"Fink","year":"2006","journal-title":"Acc.\nChem. Res."},{"issue":"6645","key":"2026083023172351500_cit18","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1038\/42166","article-title":"\u03b1-Synuclein\nin Lewy bodies","volume":"388","author":"Spillantini","year":"1997","journal-title":"Nature"},{"issue":"11","key":"2026083023172351500_cit19","doi-asserted-by":"publisher","first-page":"6469","DOI":"10.1073\/pnas.95.11.6469","article-title":"\u03b1-Synuclein\nin filamentous inclusions of Lewy bodies from Parkinson\u2019s disease\nand dementia with Lewy bodies","volume":"95","author":"Spillantini","year":"1998","journal-title":"Proc. Natl. Acad.\nSci. U. S. A."},{"issue":"2","key":"2026083023172351500_cit20","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1007\/s00401-010-0711-0","article-title":"The synaptic\npathology of \u03b1-synuclein aggregation in dementia with Lewy bodies,\nParkinson\u2019s disease and Parkinson\u2019s disease dementia","volume":"120","author":"Schulz-Schaeffer","year":"2010","journal-title":"Acta Neuropathol."},{"issue":"7825","key":"2026083023172351500_cit21","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1038\/s41586-020-2317-6","article-title":"Structures\nof \u03b1-synuclein filaments from multiple system atrophy","volume":"585","author":"Schweighauser","year":"2020","journal-title":"Nature"},{"issue":"1","key":"2026083023172351500_cit22","doi-asserted-by":"publisher","first-page":"29","DOI":"10.4103\/1735-1995.181989","article-title":"Alpha-synuclein\nstructure, functions, and interactions","volume":"21","author":"Emamzadeh","year":"2016","journal-title":"J. Res.\nMed. Sci."},{"issue":"2","key":"2026083023172351500_cit23","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1038\/ng0298-106","article-title":"Ala30Pro mutation\nin the gene encoding \u03b1-synuclein in Parkinson\u2019s\ndisease","volume":"18","author":"Kru\u0308ger","year":"1998","journal-title":"Nat. Genet."},{"issue":"2","key":"2026083023172351500_cit24","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1002\/ana.10795","article-title":"The new mutation, E46K, of \u03b1-synuclein\ncauses parkinson and Lewy body dementia","volume":"55","author":"Zarranz","year":"2004","journal-title":"Ann.\nNeurol."},{"issue":"11","key":"2026083023172351500_cit25","doi-asserted-by":"publisher","first-page":"1062","DOI":"10.1212\/WNL.0b013e31828727ba","article-title":"A novel \u03b1-synuclein\nmissense mutation in Parkinson disease","volume":"80","author":"Proukakis","year":"2013","journal-title":"Neurology"},{"key":"2026083023172351500_cit26","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1007\/s00401-013-1096-7","article-title":"\u03b1-Synucleinopathy\nassociated with G51D SNCA mutation:\na link between Parkinson\u2019s disease and multiple system atrophy?","volume":"125","author":"Kiely","year":"2013","journal-title":"Acta Neuropathol."},{"issue":"5321","key":"2026083023172351500_cit27","doi-asserted-by":"publisher","first-page":"2045","DOI":"10.1126\/science.276.5321.2045","article-title":"Mutation\nin the \u03b1-synuclein gene identified in\nfamilies with Parkinson\u2019s disease","volume":"276","author":"Polymeropoulos","year":"1997","journal-title":"Science"},{"key":"2026083023172351500_cit28","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1007\/s11910-017-0737-y","article-title":"\u03b1-Synuclein\nand parkinsonism:\nupdates and future perspectives","volume":"17","author":"Rosborough","year":"2017","journal-title":"Curr. Neurol.\nNeurosci. Rep."},{"issue":"5","key":"2026083023172351500_cit29","doi-asserted-by":"publisher","first-page":"726","DOI":"10.3390\/biom13050726","article-title":"Distinct effects\nof familial Parkinson\u2019s disease-associated mutations on \u03b1-synuclein\nphase separation and amyloid aggregation","volume":"13","author":"Xu","year":"2023","journal-title":"Biomolecules"},{"issue":"9","key":"2026083023172351500_cit30","doi-asserted-by":"publisher","first-page":"7800","DOI":"10.1074\/jbc.M411638200","article-title":"The E46K mutation\nin \u03b1-synuclein increases amyloid fibril formation","volume":"280","author":"Greenbaum","year":"2005","journal-title":"J. Biol. Chem."},{"issue":"39","key":"2026083023172351500_cit31","doi-asserted-by":"publisher","first-page":"E8274","DOI":"10.1073\/pnas.1703420114","article-title":"E46K \u03b1-synuclein pathological\nmutation causes cell-autonomous toxicity without altering protein\nturnover or aggregation","volume":"114","author":"I\u0301n\u0303igo-Marco","year":"2017","journal-title":"Proc. Natl. Acad. Sci.\nU. S. A."},{"key":"2026083023172351500_cit32","doi-asserted-by":"publisher","DOI":"10.7554\/elife.36402","article-title":"Cryo-EM structure\nof alpha-synuclein fibrils","volume":"7","author":"Guerrero-Ferreira","year":"2018","journal-title":"eLife"},{"issue":"1","key":"2026083023172351500_cit33","doi-asserted-by":"publisher","first-page":"3609","DOI":"10.1038\/s41467-018-05971-2","article-title":"Cryo-EM of full-length\n\u03b1-synuclein reveals fibril polymorphs with a common structural\nkernel","volume":"9","author":"Li","year":"2018","journal-title":"Nat. Commun."},{"key":"2026083023172351500_cit34","doi-asserted-by":"publisher","DOI":"10.7554\/elife.48907","article-title":"Two new polymorphic structures of human full-length\nalpha-synuclein fibrils solved by cryo-electron microscopy","volume":"8","author":"Guerrero-Ferreira","year":"2019","journal-title":"eLife"},{"issue":"7","key":"2026083023172351500_cit35","doi-asserted-by":"publisher","first-page":"3592","DOI":"10.1073\/pnas.1917914117","article-title":"The \u03b1-synuclein\nhereditary mutation E46K unlocks a more stable, pathogenic fibril\nstructure","volume":"117","author":"Boyer","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"1","key":"2026083023172351500_cit36","doi-asserted-by":"publisher","first-page":"2643","DOI":"10.1038\/s41467-020-16386-3","article-title":"Parkinson\u2019s\ndisease associated mutation E46K of \u03b1-synuclein\ntriggers the formation of a distinct fibril structure","volume":"11","author":"Zhao","year":"2020","journal-title":"Nat. Commun."},{"issue":"1","key":"2026083023172351500_cit37","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0060006","article-title":"Conformational\nequilibria in monomeric \u03b1-synuclein at the single-molecule level","volume":"6","author":"Sandal","year":"2008","journal-title":"PLoS Biol."},{"issue":"9","key":"2026083023172351500_cit38","doi-asserted-by":"publisher","first-page":"3048","DOI":"10.1016\/j.bpj.2010.08.056","article-title":"Single Molecule Characterization of \u03b1-Synuclein\nin Aggregation-Prone States","volume":"99","author":"Trexler","year":"2010","journal-title":"Biophys. J."},{"issue":"7588","key":"2026083023172351500_cit39","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/nature16531","article-title":"Structural\ndisorder\nof monomeric \u03b1-synuclein persists in mammalian cells","volume":"530","author":"Theillet","year":"2016","journal-title":"Nature"},{"issue":"10","key":"2026083023172351500_cit40","doi-asserted-by":"publisher","first-page":"3859","DOI":"10.1021\/ja411577t","article-title":"The role of stable \u03b1-synuclein oligomers in the molecular events\nunderlying amyloid formation","volume":"136","author":"Lorenzen","year":"2014","journal-title":"J. Am. Chem. Soc."},{"issue":"5","key":"2026083023172351500_cit41","doi-asserted-by":"publisher","first-page":"1048","DOI":"10.1016\/j.cell.2012.03.037","article-title":"Direct\nobservation of the interconversion of\nnormal and toxic forms of \u03b1-synuclein","volume":"149","author":"Cremades","year":"2012","journal-title":"Cell"},{"key":"2026083023172351500_cit42","volume-title":"Chapter Three - Structural\nCharacteristics of \u03b1-Synuclein Oligomers","author":"Cremades","year":"2017"},{"issue":"1","key":"2026083023172351500_cit43","doi-asserted-by":"publisher","first-page":"7083","DOI":"10.1038\/s41467-024-50692-4","article-title":"\u03b1-Synuclein oligomers form by secondary\nnucleation","volume":"15","author":"Xu","year":"2024","journal-title":"Nat. Commun."},{"issue":"9","key":"2026083023172351500_cit44","doi-asserted-by":"publisher","first-page":"1940","DOI":"10.1016\/j.bpj.2012.09.032","article-title":"The conformational\nensembles of \u03b1-synuclein\nand tau: combining single-molecule FRET and simulations","volume":"103","author":"Nath","year":"2012","journal-title":"Biophys. J."},{"issue":"24","key":"2026083023172351500_cit45","doi-asserted-by":"publisher","first-page":"243142","DOI":"10.1063\/1.4936910","article-title":"Transient \u03b2-hairpin\nformation\nin \u03b1-synuclein monomer revealed by coarse-grained molecular\ndynamics simulation","volume":"143","author":"Yu","year":"2015","journal-title":"J. Chem. Phys."},{"issue":"3","key":"2026083023172351500_cit46","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.1021\/acs.jcim.0c01056","article-title":"Dimerization of \u03b1-Synuclein fragments studied\nby isothermal\u2013isobaric replica-permutation molecular dynamics\nsimulation","volume":"61","author":"Yamauchi","year":"2021","journal-title":"J. Chem. Inf. Model."},{"issue":"11","key":"2026083023172351500_cit47","doi-asserted-by":"publisher","first-page":"4228","DOI":"10.1021\/acs.macromol.1c02550","article-title":"Microstructural\norganization in \u03b1-synuclein solutions","volume":"55","author":"Das","year":"2022","journal-title":"Macromolecules"},{"key":"2026083023172351500_cit48","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1016\/j.sbi.2020.12.012","article-title":"Physics-based computational\nand theoretical\napproaches to intrinsically disordered proteins","volume":"67","author":"Shea","year":"2021","journal-title":"Curr. Opin. Struct. 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