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Effective therapeutic intervention requires residue-resolved structural information on the early aggregation intermediates that precede amyloid formation. However, these transient and heterogeneous species remain poorly characterized because of their dynamic nature and the limitations of conventional structural approaches. Here, we employ a multisite fluorescence approach to obtain residue-specific insights into the misfolding and aggregation pathway of the nucleic acid-binding domain of TDP-43. Using a library of single-tryptophan\u2013single-cysteine mutants combined with site-selective labeling, we systematically probe intramolecular distances, local solvation, conformational rigidity, and structural fluctuations across native, molten globule, oligomeric, and amyloid states. The results reveal that the early amyloidogenic molten globule retains native-like secondary structure but undergoes heterogeneous structural reorganization, including simultaneous local expansion and compaction, as revealed by multisite Fo\u0308rster resonance energy transfer. Residue-specific analyses also identify early unfolding sites and regions that progressively become incorporated into the amyloid core. These findings provide a residue-resolved view of the structural transitions that link native conformations to aggregation-prone states and establish a framework for understanding early events in TDP-43 misfolding.<\/jats:p>","DOI":"10.1021\/acs.biochem.6c00438","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T13:01:57Z","timestamp":1789477317000},"page":"3003-3016","source":"Crossref","is-referenced-by-count":0,"title":["Residue-Resolved\nMapping of Heterogeneous Structural\nOrganization during Native-to-Amyloid Transition of an Amyloidogenic\nProtein"],"prefix":"10.1021","volume":"65","author":[{"given":"Sonal R.","family":"More","sequence":"first","affiliation":[{"name":"CSIR-National Chemical Laboratory , , Dr Homi Bhabha Road , ,","place":["Pune, India, 411008"]},{"name":"Academy of Scientific and Innovative Research (AcSIR) , ,","place":["Ghaziabad, India, 201002"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4044-7804","authenticated-orcid":true,"given":"Prajna","family":"Mishra","sequence":"additional","affiliation":[{"name":"CSIR-National Chemical Laboratory , , Dr Homi Bhabha Road , ,","place":["Pune, India, 411008"]},{"name":"Academy of Scientific and Innovative Research (AcSIR) , ,","place":["Ghaziabad, India, 201002"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1339-7409","authenticated-orcid":true,"given":"Santosh Kumar","family":"Jha","sequence":"additional","affiliation":[{"name":"CSIR-National Chemical Laboratory , , Dr Homi Bhabha Road , ,","place":["Pune, India, 411008"]},{"name":"Academy of Scientific and Innovative Research (AcSIR) , ,","place":["Ghaziabad, India, 201002"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"issue":"4","key":"2026100608065202500_cit1","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1016\/j.cell.2022.12.032","article-title":"Hallmarks of Neurodegenerative Diseases","volume":"186","author":"Wilson","year":"2023","journal-title":"Cell"},{"issue":"6645","key":"2026100608065202500_cit2","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1038\/42166","article-title":"\u03b1-Synuclein in Lewy Bodies","volume":"388","author":"Spillantini","year":"1997","journal-title":"Nature"},{"issue":"4","key":"2026100608065202500_cit3","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1007\/BF00308809","article-title":"Neuropathological Stageing\nof Alzheimer-Related Changes","volume":"82","author":"Braak","year":"1991","journal-title":"Acta Neuropathol."},{"issue":"1","key":"2026100608065202500_cit4","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1006\/jmbi.1994.1704","article-title":"Conformation and Fibrillogenesis\nof Alzheimer A Beta Peptides with Selected Substitution of Charged\nResidues","volume":"244","author":"Fraser","year":"1994","journal-title":"J. Mol. Biol."},{"issue":"3","key":"2026100608065202500_cit5","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1016\/j.bbrc.2006.10.093","article-title":"TDP-43 Is a Component of Ubiquitin-Positive\nTau-Negative Inclusions in Frontotemporal Lobar Degeneration and Amyotrophic\nLateral Sclerosis","volume":"351","author":"Arai","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"issue":"5796","key":"2026100608065202500_cit6","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1126\/science.1134108","article-title":"Ubiquitinated TDP-43 in Frontotemporal Lobar\nDegeneration and Amyotrophic Lateral Sclerosis","volume":"314","author":"Neumann","year":"2006","journal-title":"Science"},{"issue":"5","key":"2026100608065202500_cit7","first-page":"185","article-title":"Diffuse Type of Lewy\nBody Disease: Progressive Dementia with Abundant Cortical Lewy Bodies\nand Senile Changes of Varying Degree--a New Disease?","volume":"3","author":"Kosaka","year":"1984","journal-title":"Clin. Neuropathol."},{"issue":"1","key":"2026100608065202500_cit8","doi-asserted-by":"publisher","first-page":"26","DOI":"10.4161\/pri.1.1.4056","article-title":"Aggregation of Expanded Huntingtin\nin the Brains of Patients With Huntington Disease","volume":"1","author":"Hoffner","year":"2007","journal-title":"Prion"},{"issue":"Volume 47, 2013","key":"2026100608065202500_cit9","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1146\/annurev-genet-110711-155524","article-title":"Biology\nand Genetics of Prions Causing Neurodegeneration","volume":"47","author":"Prusiner","year":"2013","journal-title":"Annu. Rev. Genet."},{"issue":"7","key":"2026100608065202500_cit10","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a028035","article-title":"Pathology of Neurodegenerative\nDiseases","volume":"9","author":"Dugger","year":"2017","journal-title":"Cold Spring Harb Perspect Biol."},{"issue":"6","key":"2026100608065202500_cit11","doi-asserted-by":"publisher","first-page":"4200","DOI":"10.1529\/biophysj.104.049700","article-title":"Detection and Characterization of\nAggregates, Prefibrillar Amyloidogenic Oligomers, and Protofibrils\nUsing Fluorescence Spectroscopy","volume":"88","author":"Lindgren","year":"2005","journal-title":"Biophys. J."},{"issue":"8","key":"2026100608065202500_cit12","doi-asserted-by":"publisher","first-page":"2752","DOI":"10.1021\/bi051426z","article-title":"Characterization of Oligomers during \u03b1-Synuclein\nAggregation Using Intrinsic Tryptophan Fluorescence","volume":"45","author":"Dusa","year":"2006","journal-title":"Biochemistry"},{"issue":"6","key":"2026100608065202500_cit13","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1021\/acs.biochem.8b01013","article-title":"The Folding and\nAggregation Energy Landscapes of Tethered\nRRM Domains of Human TDP-43 Are Coupled via a Metastable Molten Globule-like\nOligomer","volume":"58","author":"Pillai","year":"2019","journal-title":"Biochemistry"},{"issue":"3","key":"2026100608065202500_cit14","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1021\/acs.biochem.9b00780","article-title":"Early Metastable\nAssembly during the Stress-Induced\nFormation of Worm-like Amyloid Fibrils of Nucleic Acid Binding Domains\nof TDP-43","volume":"59","author":"Pillai","year":"2020","journal-title":"Biochemistry"},{"key":"2026100608065202500_cit15","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.44698","article-title":"Monitoring\nSite-Specific Conformational Changes in\nReal-Time Reveals a Misfolding Mechanism of the Prion Protein","volume":"8","author":"Sengupta","year":"2019","journal-title":"eLife"},{"key":"2026100608065202500_cit16","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpc.2023.106972","article-title":"Shapeshifter TDP-43: Molecular Mechanism of Structural\nPolymorphism, Aggregation, Phase Separation and Their Modulators","volume":"295","author":"Doke","year":"2023","journal-title":"Biophys. Chem."},{"issue":"12","key":"2026100608065202500_cit17","doi-asserted-by":"publisher","first-page":"912","DOI":"10.1038\/s41580-023-00647-2","article-title":"Mechanisms and Pathology\nof Protein\nMisfolding and Aggregation","volume":"24","author":"Louros","year":"2023","journal-title":"Nat. Rev. Mol. Cell\nBiol."},{"issue":"7","key":"2026100608065202500_cit18","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1038\/s41594-019-0248-4","article-title":"Cryo-EM\nStructures of Four Polymorphic TDP-43 Amyloid Cores","volume":"26","author":"Cao","year":"2019","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2026100608065202500_cit19","doi-asserted-by":"publisher","first-page":"903","DOI":"10.1038\/s41594-024-01252-3","article-title":"Cryo-EM Structures of\nAmyloid-\u03b2 and Tau\nFilaments in Down Syndrome","volume":"31","author":"Fernandez","year":"2024","journal-title":"Nat. Struct. Mol.\nBiol."},{"key":"2026100608065202500_cit20","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1038\/nature23002","article-title":"Cryo-EM Structures of\nTau Filaments from Alzheimer\u2019s Disease","volume":"547","author":"Fitzpatrick","year":"2017","journal-title":"Nature"},{"issue":"7043","key":"2026100608065202500_cit21","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1038\/nature03680","article-title":"Structure of the Cross-\u03b2 Spine\nof Amyloid-like Fibrils","volume":"435","author":"Nelson","year":"2005","journal-title":"Nature"},{"issue":"9","key":"2026100608065202500_cit22","doi-asserted-by":"publisher","first-page":"4897","DOI":"10.1073\/pnas.97.9.4897","article-title":"Fiber Diffraction\nof Synthetic Alpha-Synuclein Filaments Shows Amyloid-like Cross-Beta\nConformation","volume":"97","author":"Serpell","year":"2000","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"issue":"8","key":"2026100608065202500_cit23","doi-asserted-by":"publisher","first-page":"5591","DOI":"10.1073\/pnas.042681399","article-title":"Amyloid Fibers Are\nWater-Filled Nanotubes","volume":"99","author":"Perutz","year":"2002","journal-title":"Proc. Natl. Acad. Sci.\nU.S.A."},{"issue":"8","key":"2026100608065202500_cit24","doi-asserted-by":"publisher","first-page":"989","DOI":"10.1016\/S0969-2126(96)00104-9","article-title":"Synchrotron X-Ray Studies Suggest That the Core of\nthe Transthyretin Amyloid Fibril Is a Continuous Beta-Sheet Helix","volume":"4","author":"Blake","year":"1996","journal-title":"Structure"},{"issue":"7143","key":"2026100608065202500_cit25","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1038\/nature05695","article-title":"Atomic Structures of\nAmyloid Cross-\u03b2 Spines Reveal Varied Steric Zippers","volume":"447","author":"Sawaya","year":"2007","journal-title":"Nature"},{"issue":"1","key":"2026100608065202500_cit26","doi-asserted-by":"publisher","first-page":"30","DOI":"10.3390\/diseases11010030","article-title":"Protein\nMisfolding and Aggregation in Proteinopathies: Causes, Mechanism and\nCellular Response","volume":"11","author":"Ajmal","year":"2023","journal-title":"Diseases"},{"key":"2026100608065202500_cit27","doi-asserted-by":"publisher","first-page":"25","DOI":"10.3389\/fnmol.2019.00025","article-title":"Molecular\nMechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral\nSclerosis","volume":"12","author":"Prasad","year":"2019","journal-title":"Front. Mol. Neurosci."},{"issue":"11","key":"2026100608065202500_cit28","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1177\/16.11.673","article-title":"X-Ray Diffraction\nStudies on Amyloid Filaments","volume":"16","author":"Eanes","year":"1968","journal-title":"J. Histochem Cytochem."},{"issue":"1","key":"2026100608065202500_cit29","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-04116-9","article-title":"Femtosecond X-Ray Coherent\nDiffraction of Aligned Amyloid Fibrils on Low Background Graphene","volume":"9","author":"Seuring","year":"2018","journal-title":"Nat. Commun."},{"issue":"1","key":"2026100608065202500_cit30","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1146\/annurev.physchem.47.1.369","article-title":"Insights into Protein Folding from\nNmr","volume":"47","author":"Dyson","year":"1996","journal-title":"Annu. Rev. Phys. Chem."},{"key":"2026100608065202500_cit31","doi-asserted-by":"publisher","first-page":"5356","DOI":"10.3389\/fmolb.2021.761227","article-title":"NMR Studies\nof Tau Protein in Tauopathies","volume":"8","author":"Kitoka","year":"2021","journal-title":"Front. Mol. Biosci."},{"key":"2026100608065202500_cit32","doi-asserted-by":"publisher","first-page":"552","DOI":"10.3389\/fmolb.2023.1148302","article-title":"Structural Polymorphism of the Low-Complexity\nC-Terminal Domain of TDP-43 Amyloid Aggregates Revealed by Solid-State\nNMR","volume":"10","author":"Shenoy","year":"2023","journal-title":"Front. Mol. Biosci."},{"key":"2026100608065202500_cit33","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1146\/annurev-physchem-032210-103539","article-title":"Solid State\nNMR Studies of Amyloid Fibril Structure","volume":"62","author":"Tycko","year":"2011","journal-title":"Annu.\nRev. Phys. Chem."},{"issue":"7","key":"2026100608065202500_cit34","doi-asserted-by":"publisher","first-page":"3412","DOI":"10.1021\/jacs.9b10736","article-title":"Solid-State NMR\nReveals the Structural Transformation of the TDP-43\nAmyloidogenic Region upon Fibrillation","volume":"142","author":"Zhuo","year":"2020","journal-title":"J. Am.\nChem. Soc."},{"key":"2026100608065202500_cit35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ssnmr.2017.10.001","article-title":"Insights into Protein Misfolding and Aggregation Enabled\nby Solid-State NMR Spectroscopy","volume":"88","author":"van der Wel","year":"2017","journal-title":"Solid State\nNucl. Magn Reson"},{"issue":"24","key":"2026100608065202500_cit36","doi-asserted-by":"publisher","first-page":"17082","DOI":"10.1016\/S0021-9258(18)41896-0","article-title":"Mass Spectrometry\nof Purified Amyloid Beta Protein in Alzheimer\u2019s Disease","volume":"267","author":"Mori","year":"1992","journal-title":"J. Biol. Chem."},{"issue":"52","key":"2026100608065202500_cit37","doi-asserted-by":"publisher","first-page":"37479","DOI":"10.1074\/jbc.M706714200","article-title":"Exploring\nthe Cooperativity of the Fast Folding Reaction\nof a Small Protein Using Pulsed Thiol Labeling and Mass Spectrometry","volume":"282","author":"Jha","year":"2007","journal-title":"J. Biol. Chem."},{"issue":"8","key":"2026100608065202500_cit38","doi-asserted-by":"publisher","first-page":"1072","DOI":"10.1021\/ar9002784","article-title":"Structure\nand Intermolecular Dynamics of Aggregates Populated during Amyloid\nFibril Formation Studied by Hydrogen\/Deuterium Exchange","volume":"43","author":"Carulla","year":"2010","journal-title":"Acc. Chem. Res."},{"issue":"1","key":"2026100608065202500_cit39","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1007\/s13361-017-1815-8","article-title":"Probing Conformational Dynamics of\nTau Protein by Hydrogen\/Deuterium Exchange Mass Spectrometry","volume":"29","author":"Huang","year":"2018","journal-title":"J. Am. Soc. Mass Spectrom."},{"issue":"1","key":"2026100608065202500_cit40","doi-asserted-by":"publisher","first-page":"10","DOI":"10.2183\/pjab.93.002","article-title":"Folding of\nApomyoglobin: Analysis of Transient Intermediate Structure during\nRefolding Using Quick Hydrogen Deuterium Exchange and NMR","volume":"93","author":"Nishimura","year":"2017","journal-title":"Proc. Jpn. Academy Ser. B: Phys. Biological Sci."},{"issue":"9","key":"2026100608065202500_cit41","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1038\/s41594-021-00646-x","article-title":"Cryo-EM\nStructures of hIAPP Fibrils\nSeeded by Patient-Extracted Fibrils Reveal New Polymorphs and Conserved\nFibril Cores","volume":"28","author":"Cao","year":"2021","journal-title":"Nat. Struct Mol. Biol."},{"key":"2026100608065202500_cit42","doi-asserted-by":"publisher","first-page":"e36402","DOI":"10.7554\/eLife.36402","article-title":"Cryo-EM Structure of\n\u03b1-Synuclein Fibrils","volume":"8","author":"Guerrero-Ferreira","year":"2019","journal-title":"eLife"},{"issue":"1","key":"2026100608065202500_cit43","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21912-y","article-title":"Cryo-EM Structure of Amyloid Fibrils\nFormed by the Entire Low Complexity Domain of TDP-43","volume":"12","author":"Li","year":"2021","journal-title":"Nat. Commun."},{"issue":"6577","key":"2026100608065202500_cit44","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1126\/science.abm7285","article-title":"Cryo-EM Structures of\nAmyloid-\u03b2 42 Filaments\nfrom Human Brains","volume":"375","author":"Yang","year":"2022","journal-title":"Science"},{"issue":"1","key":"2026100608065202500_cit45","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-44489-0","article-title":"Cryo-EM Observation\nof the Amyloid Key Structure of Polymorphic TDP-43 Amyloid Fibrils","volume":"15","author":"Sharma","year":"2024","journal-title":"Nat. Commun."},{"key":"2026100608065202500_cit46","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1039\/D2FD00034B","article-title":"High-Throughput Cryo-EM Structure\nDetermination of\nAmyloids","volume":"240","author":"Lo\u0308vestam","year":"2022","journal-title":"Faraday Discuss."},{"issue":"4","key":"2026100608065202500_cit47","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1016\/j.jmb.2006.02.006","article-title":"Characterization\nof the Formation of Amyloid Protofibrils from Barstar by Mapping Residue-Specific\nFluorescence Dynamics","volume":"358","author":"Mukhopadhyay","year":"2006","journal-title":"J. Mol. Biol."},{"issue":"23","key":"2026100608065202500_cit48","doi-asserted-by":"publisher","first-page":"11819","DOI":"10.1021\/acs.chemrev.9b00404","article-title":"Interrogating Amyloid Aggregates\nUsing Fluorescent Probes","volume":"119","author":"Aliyan","year":"2019","journal-title":"Chem. Rev."},{"issue":"3","key":"2026100608065202500_cit49","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1021\/bi101440c","article-title":"Exploration\nof the Correlation between Solvation Dynamics and Internal Dynamics\nof a Protein","volume":"50","author":"Jha","year":"2011","journal-title":"Biochemistry"},{"issue":"3","key":"2026100608065202500_cit50","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1016\/j.jmb.2009.08.053","article-title":"Characterization of the Heterogeneity\nand Specificity of Interpolypeptide Interactions in Amyloid Protofibrils\nby Measurement of Site-Specific Fluorescence Anisotropy Decay Kinetics","volume":"393","author":"Jha","year":"2009","journal-title":"J. Mol. Biol."},{"issue":"10","key":"2026100608065202500_cit51","doi-asserted-by":"publisher","first-page":"1565","DOI":"10.1038\/s41557-025-01889-7","article-title":"High-Throughput\nDiscovery of Fluoroprobes That Recognize\nAmyloid Fibril Polymorphs","volume":"17","author":"Carroll","year":"2025","journal-title":"Nat. Chem."},{"key":"2026100608065202500_cit52","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadva.2023.100091","article-title":"Applications of Fluorescence Spectroscopy in Protein Conformational\nChanges and Intermolecular Contacts","volume":"3","author":"Dos Santos Rodrigues","year":"2023","journal-title":"BBA Advances"},{"key":"2026100608065202500_cit53","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1007\/s10895-010-0648-5","article-title":"Characterization\nof Protein Aggregates\nby Fluorescence Spectroscopy","volume":"20","author":"Hawe","year":"2010","journal-title":"J. Fluoresc."},{"issue":"7","key":"2026100608065202500_cit54","doi-asserted-by":"publisher","first-page":"1487","DOI":"10.1007\/s11095-007-9516-9","article-title":"Extrinsic\nFluorescent Dyes as Tools\nfor Protein Characterization","volume":"25","author":"Hawe","year":"2008","journal-title":"Pharm. Res."},{"key":"2026100608065202500_cit55","doi-asserted-by":"publisher","first-page":"1487","DOI":"10.1007\/s11095-007-9516-4","article-title":"Extrinsic Fluorescence to Assess\nProtein Aggregation and Stability","volume":"25","author":"Hawe","year":"2008","journal-title":"Pharm. Res."},{"issue":"30","key":"2026100608065202500_cit56","doi-asserted-by":"publisher","first-page":"22645","DOI":"10.1074\/jbc.M000756200","article-title":"A Conformation Change in the Carboxyl\nTerminus of Alzheimer\u2019s Abeta (1\u201340) Accompanies the\nTransition from Dimer to Fibril as Revealed by Fluorescence Quenching\nAnalysis","volume":"275","author":"Garzon-Rodriguez","year":"2000","journal-title":"J. Biol. 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