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Here, we present a novel single\u2010molecule technique to efficiently analyze \u03b1Syn monomer with\n                    <jats:italic>Mycobacterium smegmatis<\/jats:italic>\n                    porin A (MspA) nanopores. The nanopore signals elicited by \u03b1Syn consist of three distinct, reproducible current levels. Notably, through systematic measurement of \u03b1Syn fragments, reference peptide with \u03b1\u2010helical structure and molecular dynamics simulation study, we demonstrate that these current levels correspond to \u03b1\u2010helical and random\u2010coil structures within the protein. The \u03b1\u2010helical structures are successfully assigned to the specific \u03b1Syn subdomains. A biophysical parameter figure matrix derived from the \u03b1Syn signals is further generated and readily applied to profile the structural heterogeneity of monomeric \u03b1Syn variants. These results establish that MspA nanopores can directly sense the formation of \u03b1\u2010helical structure in individual \u03b1Syn monomer, which advances our capability to investigate this highly flexible pathological protein and may contribute to elucidating its misfolding mechanism.\n                  <\/jats:p>","DOI":"10.1002\/anie.202523298","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T06:49:17Z","timestamp":1776149357000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Profiling the Structural Heterogeneity of Monomeric \u03b1\u2010Synuclein From the Single\u2010Molecule Level Using MspA Nanopores"],"prefix":"10.1002","volume":"65","author":[{"given":"Xiaoya","family":"Zhang","sequence":"first","affiliation":[{"name":"Research and Innovation Center, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Human Phenome Institute, Zhangjiang Fudan International Innovation Center Fudan University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinpei","family":"Wang","sequence":"additional","affiliation":[{"name":"Research and Innovation Center, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Human Phenome Institute, Zhangjiang Fudan International Innovation Center Fudan University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Research and Innovation Center, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Human Phenome Institute, Zhangjiang Fudan International Innovation Center Fudan University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Liu","sequence":"additional","affiliation":[{"name":"Research and Innovation Center, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Human Phenome Institute, 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