{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T13:01:12Z","timestamp":1791291672104,"version":"4.1.0"},"reference-count":49,"publisher":"American Chemical Society (ACS)","issue":"19","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["P30CA016086"],"award-info":[{"award-number":["P30CA016086"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100023043","name":"State of Florida","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100023043","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM163276"],"award-info":[{"award-number":["GM163276"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000078","name":"Division of Materials Research","doi-asserted-by":"publisher","award":["DMR-1644779"],"award-info":[{"award-number":["DMR-1644779"]}],"id":[{"id":"10.13039\/100000078","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The aggregation of transthyretin (TTR) is a hallmark of ATTR amyloidosis. Accumulating evidence suggests that metal ions, particularly Zn2+, promote TTR aggregation; however, the molecular mechanism underlying Zn2+-induced misfolding remains poorly understood. Here, we present a comprehensive biophysical characterization of Zn2+-induced misfolding of wild-type transthyretin (TTRwt) under physiologically relevant conditions. Two-dimensional 1H\/15N HSQC NMR analyses reveal that Zn2+ binding induces millisecond-time scale conformational exchange that destabilizes the native tetramer. These structural and dynamic perturbations promote the formation of small, toxic oligomeric species capable of self-propagation through the seeding of native TTR. Comparative structural analyses using solid-state NMR also show that Zn2+-induced oligomers adopt broadly native-like secondary structures, but exhibit distinct non-native molecular conformations. The early stages of misfolding were further investigated using 19F NMR of TTRwt containing fluorinated tryptophan residues. Notably, 19F NMR not only reports on Zn2+ binding but also enables direct detection of a transient monomeric intermediate generated upon tetramer dissociation, a key species in the amyloidogenic cascade. Together, these findings define the structural and dynamic basis of Zn2+-mediated TTR misfolding and establish combined solution and solid-state NMR approaches as powerful tools for probing metal-induced misfolding landscapes in TTR and related amyloidogenic proteins.<\/jats:p>","DOI":"10.1021\/acs.biochem.6c00448","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T08:02:33Z","timestamp":1789632153000},"page":"3017-3025","source":"Crossref","is-referenced-by-count":0,"title":["Zn2+-Induced Dissociation of Transthyretin\nTetramers Generates Toxic, Seeding-Active Misfolded Oligomers"],"prefix":"10.1021","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-8506-3728","authenticated-orcid":true,"given":"Robert","family":"Irving","sequence":"first","affiliation":[{"name":"East Carolina University , , ,","place":["Greenville, North Carolina, United States, 27858"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anvesh","family":"Dasari","sequence":"additional","affiliation":[{"name":"Electron Microscopy Shared Resources, Fred Hutchinson Cancer Center , , ,","place":["Seattle, Washington, United States, 98109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sy","family":"Duke","sequence":"additional","affiliation":[{"name":"East Carolina University , , ,","place":["Greenville, North Carolina, United States, 27858"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0728-095X","authenticated-orcid":true,"given":"Sungsool","family":"Wi","sequence":"additional","affiliation":[{"name":"National High Magnetic Field Laboratory (NHMFL) , , 1800 East, Paul Dirac Dr. , , ,","place":["Tallahassee, Florida, United States, 32310"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4465-4212","authenticated-orcid":true,"given":"Robert M.","family":"Hughes","sequence":"additional","affiliation":[{"name":"East Carolina University , , ,","place":["Greenville, North Carolina, United States, 27858"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne M.","family":"Spuches","sequence":"additional","affiliation":[{"name":"East Carolina University , , ,","place":["Greenville, North Carolina, United States, 27858"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0971-200X","authenticated-orcid":true,"given":"Kwang Hun","family":"Lim","sequence":"additional","affiliation":[{"name":"East Carolina University , , ,","place":["Greenville, North Carolina, United States, 27858"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"2026100608064867600_cit1","doi-asserted-by":"publisher","first-page":"3095","DOI":"10.1007\/s00018-009-0109-0","article-title":"Transthyretin: The servant of many masters","volume":"66","author":"Buxbaum","year":"2009","journal-title":"Cell Mol. 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Cardiol."},{"key":"2026100608064867600_cit5","doi-asserted-by":"publisher","first-page":"2843","DOI":"10.1073\/pnas.87.7.2843","article-title":"Fibril in senile\nsystemic amyloidosis is derived from normal transthyretin","volume":"87","author":"Westermark","year":"1990","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026100608064867600_cit6","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1185\/03007995.2012.754348","article-title":"THAOS -\nthe transthyretin amyloidosis\noutcomes survey: Initial report on clinical manifestations in patients\nwith hereditary and wild-type transthyretin amyloidosis","volume":"29","author":"Coelho","year":"2013","journal-title":"Curr. Med. Res. Opin."},{"issue":"Suppl 1","key":"2026100608064867600_cit7","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1080\/13506129.2003.12088568","article-title":"Transthyretin-derived\nsenile systemic amyloidosis: Clinicopathologic and structural considerations","volume":"10","author":"Westermark","year":"2003","journal-title":"Amyloid"},{"key":"2026100608064867600_cit8","doi-asserted-by":"publisher","first-page":"988","DOI":"10.1212\/WNL.47.4.988","article-title":"Massive leptomeningeal\namyloidosis associated with a Val30Met transthyretin\ngene","volume":"47","author":"Herrick","year":"1996","journal-title":"Neurology"},{"key":"2026100608064867600_cit9","doi-asserted-by":"publisher","first-page":"6470","DOI":"10.1021\/bi952501g","article-title":"The acid-mediated\ndenaturation pathway\nof transthyretin yields a conformational intermediate that can self-assemble\ninto amyloid","volume":"35","author":"Lai","year":"1996","journal-title":"Biochemistry"},{"key":"2026100608064867600_cit10","doi-asserted-by":"publisher","first-page":"17851","DOI":"10.1021\/bi981876+","article-title":"Characterization\nof the transthyretin\nacid denaturation pathways by analytical ultracentrifugation: Implications\nfor wild-type, V30M, and L55P amyloid fibril formation","volume":"37","author":"Lashuel","year":"1998","journal-title":"Biochemistry"},{"key":"2026100608064867600_cit11","doi-asserted-by":"publisher","first-page":"27207","DOI":"10.1074\/jbc.M101024200","article-title":"Tetramer\ndissociation and monomer partial unfolding precedes protofibril formation\nin amyloidogenic transthyretin variants","volume":"276","author":"Quintas","year":"2001","journal-title":"J.\nBiol. Chem."},{"key":"2026100608064867600_cit12","doi-asserted-by":"publisher","first-page":"252","DOI":"10.3390\/biom4010252","article-title":"Heavy metals\nand metalloids as a cause for protein misfolding and aggregation","volume":"4","author":"Tama\u0301s","year":"2014","journal-title":"Biomolecules"},{"key":"2026100608064867600_cit13","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1186\/s40035-020-00189-z","article-title":"Current understanding of metal ions in the pathogenesis\nof alzheimer\u2019s disease","volume":"9","author":"Wang","year":"2020","journal-title":"Translational\nNeurodegeneration"},{"key":"2026100608064867600_cit14","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1021\/jasms.2c00379","article-title":"Taking charge: Metal\nions accelerate amyloid aggregation in sequence variants of \u03b1-synuclein","volume":"34","author":"Byrd","year":"2023","journal-title":"J. Am. Soc. Mass Spectrom."},{"key":"2026100608064867600_cit15","doi-asserted-by":"publisher","first-page":"16293","DOI":"10.1038\/s41598-020-73207-9","article-title":"Metal ions\nshape \u03b1-synuclein","volume":"10","author":"Moons","year":"2020","journal-title":"Sci. Rep."},{"key":"2026100608064867600_cit16","doi-asserted-by":"publisher","first-page":"214978","DOI":"10.1016\/j.ccr.2022.214978","article-title":"Intercommunication\nbetween metal ions and amyloidogenic peptides or proteins in protein\nmisfolding disorders","volume":"478","author":"Suh","year":"2023","journal-title":"Coord. Chem. Rev."},{"key":"2026100608064867600_cit17","doi-asserted-by":"publisher","first-page":"9123","DOI":"10.1021\/bi700607z","article-title":"Characterization\nof the binding of cu(II) and zn(II)\nto transthyretin: Effects on amyloid formation","volume":"46","author":"Wilkinson-White","year":"2007","journal-title":"Biochemistry (N. 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Cardiol."},{"key":"2026100608064867600_cit20","first-page":"E6201","article-title":"Kinetic analysis\nof the multistep aggregation pathway of human transthyretin","volume-title":"Proceedings of the National Academy of Sciences","author":"Sun","year":"2018"},{"key":"2026100608064867600_cit21","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1021\/jacs.3c10083","article-title":"Probing\nthe dissociation pathway\nof a kinetically labile transthyretin mutant","volume":"146","author":"Sun","year":"2024","journal-title":"J. Am. Chem. Soc."},{"key":"2026100608064867600_cit22","doi-asserted-by":"publisher","first-page":"10533","DOI":"10.1021\/ja404584s","article-title":"Dynamic\nequilibria between monomeric and oligomeric misfolded states of the\nmammalian prion protein measured by 19F NMR","volume":"135","author":"Larda","year":"2013","journal-title":"J. Am. Chem. 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Y. )"},{"key":"2026100608064867600_cit26","doi-asserted-by":"publisher","first-page":"4627","DOI":"10.1039\/D0CC01551B","article-title":"High-resolution\nprobing of early\nevents in amyloid-\u03b2 aggregation related to alzheimer\u2019s\ndisease","volume":"56","author":"Sahoo","year":"2020","journal-title":"Chem. Commun."},{"key":"2026100608064867600_cit27","doi-asserted-by":"publisher","first-page":"5272","DOI":"10.1021\/acs.biochem.6b00649","article-title":"Solid-state NMR\nstudies reveal native-like\nbeta-sheet structures in transthyretin amyloid","volume":"55","author":"Lim","year":"2016","journal-title":"Biochemistry"},{"key":"2026100608064867600_cit28","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/S0003-2697(03)00281-1","article-title":"Spectropotentiometric analysis of metal binding to\nstructural zinc-binding sites: Accounting quantitatively for pH and\nmetal ion buffering effects","volume":"320","author":"Magyar","year":"2003","journal-title":"Anal. Biochem."},{"key":"2026100608064867600_cit29","doi-asserted-by":"publisher","first-page":"1183","DOI":"10.1007\/s00775-010-0693-3","article-title":"Application\nof isothermal titration\ncalorimetry in bioinorganic chemistry","volume":"15","author":"Grossoehme","year":"2010","journal-title":"JBIC\nJournal of Biological Inorganic Chemistry"},{"key":"2026100608064867600_cit30","doi-asserted-by":"publisher","first-page":"892","DOI":"10.1016\/j.bbagen.2015.08.018","article-title":"Dissecting\nITC data of metal ions binding to ligands and proteins","volume":"1860","author":"Johnson","year":"2016","journal-title":"Biochimica et Biophysica Acta (BBA)-General Subjects"},{"key":"2026100608064867600_cit31","doi-asserted-by":"crossref","unstructured":"Pervushin, K.; Riek, R.; Wider, G.; Wu\u0308thrich, K.\n          Attenuated\nT 2 relaxation by\nmutual cancellation of dipole\u2013dipole coupling and chemical\nshift anisotropy indicates an avenue to NMR structures of very large\nbiological macromolecules in solution. In  Proceedings of the National Academy of Sciences, 1997; Vol. 94, pp 12366\u201312371.","DOI":"10.1073\/pnas.94.23.12366"},{"key":"2026100608064867600_cit32","doi-asserted-by":"publisher","first-page":"1325","DOI":"10.1093\/bioinformatics\/btu830","article-title":"NMRFAM-SPARKY:\nEnhanced software\nfor biomolecular NMR spectroscopy","volume":"31","author":"Lee","year":"2015","journal-title":"Bioinformatics"},{"key":"2026100608064867600_cit33","doi-asserted-by":"publisher","first-page":"2325","DOI":"10.1063\/1.1534105","article-title":"13C\u20131H\ndipolar-driven 13C\u201313C\nrecoupling without 13C rf irradiation in nuclear magnetic resonance\nof rotating solids","volume":"118","author":"Takegoshi","year":"2003","journal-title":"J. Chem. Phys."},{"key":"2026100608064867600_cit34","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1006\/jmre.1999.1896","article-title":"An improved\nbroadband decoupling\nsequence for liquid crystals and solids","volume":"142","author":"Fung","year":"2000","journal-title":"J.\nMagn. Reson."},{"key":"2026100608064867600_cit35","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1385\/1-59259-809-9:313","article-title":"Using NMRView\nto visualize and analyze the NMR spectra of macromolecules","volume":"278","author":"Johnson","year":"2004","journal-title":"Methods Mol. Biol."},{"key":"2026100608064867600_cit36","doi-asserted-by":"publisher","first-page":"852","DOI":"10.1110\/ps.3180102","article-title":"Probability-based protein secondary\nstructure identification\nusing combined NMR chemical-shift data","volume":"11","author":"Wang","year":"2002","journal-title":"Protein\nSci."},{"key":"2026100608064867600_cit37","doi-asserted-by":"publisher","first-page":"9615","DOI":"10.1073\/pnas.0610313104","article-title":"Protein structure\ndetermination from NMR chemical shifts","volume":"104","author":"Cavalli","year":"2007","journal-title":"Proc.\nNatl. Acad. Sci. U. S. A."},{"key":"2026100608064867600_cit38","doi-asserted-by":"publisher","first-page":"1800","DOI":"10.1021\/acs.biochem.0c00091","article-title":"Structural characterization\nof cardiac ex vivo transthyretin amyloid: Insight into the transthyretin\nmisfolding pathway in vivo","volume":"59","author":"Dasari","year":"2020","journal-title":"Biochemistry"},{"key":"2026100608064867600_cit39","doi-asserted-by":"publisher","first-page":"31731","DOI":"10.1074\/jbc.M110.157206","article-title":"Novel Zn2\n-binding sites in human\ntransthyretin: Implications for amyloidogenesis and retinol-binding\nprotein recognition","volume":"285","author":"Palmieri","year":"2010","journal-title":"J. Biol. Chem."},{"key":"2026100608064867600_cit40","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1038\/78980","article-title":"A glimpse\nof a possible amyloidogenic intermediate of transthyretin","volume":"7","author":"Liu","year":"2000","journal-title":"Nat. Struct. Biol."},{"key":"2026100608064867600_cit41","doi-asserted-by":"publisher","first-page":"4421","DOI":"10.1021\/acs.biochem.8b00642","article-title":"NMR measurements\nreveal the structural basis of transthyretin destabilization by pathogenic\nmutations","volume":"57","author":"Leach","year":"2018","journal-title":"Biochemistry (N. Y. )"},{"key":"2026100608064867600_cit42","doi-asserted-by":"publisher","first-page":"5570","DOI":"10.1021\/acs.biochem.7b00815","article-title":"Fluorotryptophan\nincorporation modulates\nthe structure and stability of transthyretin in a site-specific manner","volume":"56","author":"Sun","year":"2017","journal-title":"Biochemistry (N. Y. )"},{"key":"2026100608064867600_cit43","doi-asserted-by":"publisher","first-page":"1854","DOI":"10.1021\/jasms.4c00170","article-title":"Water plays key roles in stabilities of wild type and\nmutant transthyretin complexes","volume":"35","author":"Lantz","year":"2024","journal-title":"J. Am. Soc.\nMass Spectrom."},{"key":"2026100608064867600_cit44","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1007\/s10858-024-00442-x","article-title":"Micromolar fluoride\ncontamination arising from glass NMR tubes and a simple solution for\nbiomolecular applications","volume":"78","author":"Matwani","year":"2024","journal-title":"J. Biomol. NMR."},{"key":"2026100608064867600_cit45","doi-asserted-by":"publisher","first-page":"S14","DOI":"10.1017\/S0007114508006818","article-title":"Indicators of zinc\nstatus at the population level: A review of the evidence","volume":"99","author":"Gibson","year":"2008","journal-title":"Br. J. Nutr."},{"key":"2026100608064867600_cit46","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1152\/physrev.00035.2014","article-title":"The physiological,\nbiochemical, and molecular roles of zinc transporters in zinc homeostasis\nand metabolism","volume":"95","author":"Kambe","year":"2015","journal-title":"Physiol. Rev."},{"key":"2026100608064867600_cit47","doi-asserted-by":"publisher","first-page":"5","DOI":"10.3389\/fphys.2019.00005","article-title":"The extracellular\nprotein, transthyretin is an oxidative stress biomarker","volume":"10","author":"Sharma","year":"2019","journal-title":"Front. Physiol."},{"key":"2026100608064867600_cit48","doi-asserted-by":"publisher","first-page":"7365","DOI":"10.1021\/bi049621l","article-title":"Transthyretin aggregation\nunder partially denaturing conditions is a downhill polymerization","volume":"43","author":"Hurshman","year":"2004","journal-title":"Biochemistry"},{"key":"2026100608064867600_cit49","doi-asserted-by":"publisher","first-page":"E6741","DOI":"10.1073\/pnas.1805131115","article-title":"Amyloid seeding of transthyretin\nby ex vivo cardiac fibrils and its inhibition","volume":"115","author":"Saelices","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U. S. A."}],"container-title":["Biochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.biochem.6c00448","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/bichaw\/article-pdf\/65\/19\/3017\/68540085\/acs.biochem.6c00448.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/bichaw\/article-pdf\/65\/19\/3017\/68540085\/acs.biochem.6c00448.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T12:49:28Z","timestamp":1791290968000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/bichaw\/article\/65\/19\/3017\/5431803\/Zn2-Induced-Dissociation-of-Transthyretin"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,17]]},"references-count":49,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,9,17]]},"published-print":{"date-parts":[[2026,10,6]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.biochem.6c00448","relation":{},"ISSN":["0006-2960","1520-4995"],"issn-type":[{"value":"0006-2960","type":"print"},{"value":"1520-4995","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,17]]}}}