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However, understanding the specific role of phosphorylation at each site, or how multiple phosphorylation sites interact, has been challenging. Herein, we present an efficient method that leverages an organometallic Pd-complex to site-specifically attach phosphomimetic groups via Cys-arylation, closely mimicking natural phosphorylation. Using this approach, we successfully incorporated native-like tyrosine phosphorylation mimics into cysteine-containing proteins like synthetic transcription factor Max and recombinant aSyn, in good yields. To demonstrate the method\u2019s versatility, we created a focused library of mono-, di-, and triphosphorylated aSyn analogues. This development enabled, for the first time, the investigation of the effect of site-specific phosphorylation at multiple C-terminal tyrosine residues on aSyn fibrillization and aggregation. Our results show that monophosphorylation at any of the C-terminal sites has little effect on aggregation, while di- and triphosphorylation slows down the process, extending the lag phase compared to wild-type aSyn. Additionally, phosphorylation at Y39 reduces the seeding activity of aSyn fibrils by almost 2\u20134-fold in both mammalian and neuronal models of synuclein pathology. Overall, our strategy provides a rapid, selective, and scalable way to introduce aromatic PTMs, producing homogeneous protein libraries essential for mechanistic studies, biomarker development, and exploring the therapeutic potential of targeting aSyn-phosphorylation for PD and related disorders.<\/jats:p>","DOI":"10.1021\/jacs.6c12345","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:02:00Z","timestamp":1787025720000},"page":"37286-37297","source":"Crossref","is-referenced-by-count":0,"title":["A Site-Specific\nOrganometallic Approach for Installing\nTyrosine Phosphorylation Mimics to Decipher the Role of Phosphorylation\nin \u03b1-Synuclein Aggregation and Seeding"],"prefix":"10.1021","volume":"148","author":[{"given":"Shaswati","family":"Mandal","sequence":"first","affiliation":[{"name":"E\u0301cole Polytechnique Fe\u0301de\u0301rale de Lausanne , , ,","place":["Lausanne, Switzerland, CH-1015"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxi","family":"Lin","sequence":"additional","affiliation":[{"name":"Tel Aviv University , , ,","place":["Tel Aviv, Israel, 69978"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3399-2413","authenticated-orcid":true,"given":"Anastasia V.","family":"Gemelli","sequence":"additional","affiliation":[{"name":"E\u0301cole Polytechnique Fe\u0301de\u0301rale de Lausanne , , ,","place":["Lausanne, Switzerland, CH-1015"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manjeet","family":"Singh","sequence":"additional","affiliation":[{"name":"Tel Aviv University , , ,","place":["Tel Aviv, Israel, 69978"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Laure","family":"Mahul-Mellier","sequence":"additional","affiliation":[{"name":"E\u0301cole Polytechnique Fe\u0301de\u0301rale de Lausanne , , ,","place":["Lausanne, Switzerland, CH-1015"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yllza","family":"Jasiqi","sequence":"additional","affiliation":[{"name":"E\u0301cole Polytechnique Fe\u0301de\u0301rale de Lausanne , , ,","place":["Lausanne, Switzerland, CH-1015"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bouchra","family":"Bouri","sequence":"additional","affiliation":[{"name":"E\u0301cole Polytechnique Fe\u0301de\u0301rale de Lausanne , , ,","place":["Lausanne, Switzerland, CH-1015"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4206-5908","authenticated-orcid":true,"given":"Muhammad","family":"Jbara","sequence":"additional","affiliation":[{"name":"Tel Aviv University , , ,","place":["Tel Aviv, Israel, 69978"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7682-8320","authenticated-orcid":true,"given":"Hilal A.","family":"Lashuel","sequence":"additional","affiliation":[{"name":"E\u0301cole Polytechnique Fe\u0301de\u0301rale de Lausanne , , ,","place":["Lausanne, Switzerland, CH-1015"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"issue":"3","key":"2026090312081788800_cit1a","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1038\/nchembio.2572","article-title":"The ABCs of\nPTMs","volume":"14","author":"Barber","year":"2018","journal-title":"Nat. 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Biol."},{"issue":"3","key":"2026090312081788800_cit3","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.261","article-title":"Protein posttranslational modifications\nin health and\ndiseases: Functions, regulatory mechanisms, and therapeutic implications","volume":"4","author":"Zhong","year":"2023","journal-title":"MedComm"},{"key":"2026090312081788800_cit4a","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5740","article-title":"Selective chemical protein modification","volume":"5","author":"Spicer","year":"2014","journal-title":"Nat. Commun."},{"issue":"2","key":"2026090312081788800_cit4b","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1038\/nchem.2393","article-title":"Site-selective\nprotein-modification chemistry for basic biology and drug development","volume":"8","author":"Krall","year":"2016","journal-title":"Nat. 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Parkinson\u2019s\nDis."},{"issue":"2","key":"2026090312081788800_cit15b","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1016\/0896-6273(95)90302-X","article-title":"The Precursor Protein of Non-A\u03b2 Component of\nAlzheimers Disease Amyloid Is a Presynaptic Protein of the Central\nNervous System","volume":"14","author":"Iwai","year":"1995","journal-title":"Neuron"},{"key":"2026090312081788800_cit16a","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1111\/j.1749-6632.2000.tb06900.x","article-title":"The \u03b1-synucleinopathies:\nParkinson\u2019s disease, dementia with Lewy bodies, and multiple\nsystem atrophy","volume":"920","author":"Spillantini","year":"2000","journal-title":"Ann. N. Y. Acad. Sci."},{"issue":"1","key":"2026090312081788800_cit16b","doi-asserted-by":"publisher","DOI":"10.1038\/s41531-022-00357-0","article-title":"Opportunities and\nchallenges of alpha-synuclein as a potential biomarker for Parkinson\u2019s\ndisease and other synucleinopathies","volume":"8","author":"Magalha\u0303es","year":"2022","journal-title":"npj Parkinson\u2019s\nDis."},{"issue":"5","key":"2026090312081788800_cit17a","doi-asserted-by":"publisher","first-page":"1511","DOI":"10.1073\/pnas.1808845116","article-title":"alphaSynuclein O-GlcNAcylation alters aggregation and\ntoxicity, revealing certain residues as potential inhibitors of Parkinson\u2019s\ndisease","volume":"116","author":"Levine","year":"2019","journal-title":"Proc. Natl. Acad. Sci. 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Commun."},{"issue":"2","key":"2026090312081788800_cit18","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1016\/0003-2697(89)90046-8","article-title":"Fluorometric determination\nof amyloid fibrils in vitro using the fluorescent dye, thioflavin\nT1","volume":"177","author":"Naiki","year":"1989","journal-title":"Anal. Biochem."},{"issue":"1","key":"2026090312081788800_cit19","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1111\/jnc.14955","article-title":"A simple,\nversatile and robust centrifugation-based filtration protocol for\nthe isolation and quantification of \u03b1-synuclein monomers, oligomers\nand fibrils: Towards improving experimental reproducibility in \u03b1-synuclein\nresearch","volume":"153","author":"Kumar","year":"2020","journal-title":"J. Neurochem."},{"issue":"33","key":"2026090312081788800_cit20","doi-asserted-by":"publisher","first-page":"20305","DOI":"10.1073\/pnas.1922741117","article-title":"Parkinson\u2019s\ndisease-related phosphorylation\nat Tyr39 rearranges \u03b1-synuclein amyloid fibril structure revealed\nby cryo-EM","volume":"117","author":"Zhao","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"issue":"9","key":"2026090312081788800_cit21","doi-asserted-by":"publisher","first-page":"2428","DOI":"10.1021\/acschembio.6b00539","article-title":"Semisynthetic and in Vitro Phosphorylation of Alpha-Synuclein\nat Y39 Promotes Functional Partly Helical Membrane-Bound States Resembling\nThose Induced by PD Mutations","volume":"11","author":"Dikiy","year":"2016","journal-title":"ACS Chem. Biol."},{"key":"2026090312081788800_cit22","doi-asserted-by":"crossref","unstructured":"Donzelli, S.; OSullivan, S. A.; Mahul-Mellier, A. L.; Ulusoy, A.; Fusco, G.; Kumar, S. T.; Lashuel, H. 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Neurosci."},{"issue":"11","key":"2026090312081788800_cit24a","doi-asserted-by":"publisher","first-page":"2858","DOI":"10.1093\/hmg\/ddt674","article-title":"c-Abl phosphorylates\n\u03b1-synuclein and regulates its degradation:\nimplication for \u03b1-synuclein clearance and contribution to the\npathogenesis of Parkinson\u2019s disease","volume":"23","author":"Mahul-Mellier","year":"2014","journal-title":"Hum. Mol. Genet."},{"issue":"8","key":"2026090312081788800_cit24b","doi-asserted-by":"publisher","first-page":"2970","DOI":"10.1172\/JCI85456","article-title":"Activation\nof tyrosine kinase c-Abl contributes to \u03b1-synuclein\u2013\ninduced neurodegeneration","volume":"126","author":"Brahmachari","year":"2016","journal-title":"J. Clin. Invest."},{"key":"2026090312081788800_cit25a","doi-asserted-by":"publisher","first-page":"1661","DOI":"10.1073\/pnas.0509567103","article-title":"Lewy bodies","volume":"103","author":"Shults","year":"2006","journal-title":"Proc. Natl. Acad. Sci. 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