{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T11:03:40Z","timestamp":1784545420457,"version":"3.55.0"},"reference-count":20,"publisher":"Wiley","issue":"30","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Angew Chem Int Ed"],"published-print":{"date-parts":[[2026,7,20]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    \u2010Microglobulin (\u03b22m) aggregation is central to dialysis\u2010related amyloidosis (DRA), yet the molecular triggers underlying its fibrillogenesis remain incompletely defined. Among proposed mechanisms, isoaspartate (isoAsp) formation at Asn residues has been implicated but never directly tested due to synthetic inaccessibility. Here, we report the total chemical synthesis of \u03b22m variants containing isoAsp at known in vivo hotspots, Asn\n                    <jats:sup>17<\/jats:sup>\n                    and Asn\n                    <jats:sup>42<\/jats:sup>\n                    , enabling precise structural and functional interrogation. Remarkably, the isoAsp\n                    <jats:sup>17<\/jats:sup>\n                    \u2010modified \u03b22m exhibited greater fibril formation capacity than the pathogenic \u0394N6\u2010\u03b22m variant, suggesting a previously underappreciated contribution of isoAsp\n                    <jats:sup>17<\/jats:sup>\n                    . Structural characterization was complemented by spectroscopic and TEM analyses, which demonstrated that isoAsp\n                    <jats:sup>17<\/jats:sup>\n                    promotes fibril formation. Our findings provide the first direct experimental evidence that a spontaneous post\u2010translational modification can initiate amyloidogenesis in \u03b22m, redefining the molecular basis of DRA and highlighting isoAsp as a general driver of pathological protein aggregation.\n                  <\/jats:p>","DOI":"10.1002\/anie.7045464","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T01:12:36Z","timestamp":1780967556000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Post\u2010Translational Isoaspartate Promotes Amyloid Formation in \u03b2\n                    <sub>2<\/sub>\n                    \u2010Microglobulin"],"prefix":"10.1002","volume":"65","author":[{"given":"Ryuji","family":"Kawakami","sequence":"first","affiliation":[{"name":"Institute for Protein Research The University of Osaka  Suita Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiki","family":"Takei","sequence":"additional","affiliation":[{"name":"Institute for Protein Research The University of Osaka  Suita Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masatomo","family":"So","sequence":"additional","affiliation":[{"name":"Graduate School of Agriculture Kyoto University  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshifumi","family":"Takao","sequence":"additional","affiliation":[{"name":"Institute for Protein Research The University of Osaka  Suita Osaka Japan"},{"name":"Rigaku Corporation  Akishima Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshinori","family":"Taguchi","sequence":"additional","affiliation":[{"name":"Institute for Protein Research The University of Osaka  Suita Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0916-1233","authenticated-orcid":false,"given":"Hironobu","family":"Hojo","sequence":"additional","affiliation":[{"name":"Institute for Protein Research The University of Osaka  Suita Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,8]]},"reference":[{"key":"e_1_2_6_2_1","first-page":"506","article-title":"HLA\u2010A2","volume":"329","author":"Strominger L.","year":"1987","journal-title":"Nature"},{"key":"e_1_2_6_3_1","first-page":"153","article-title":"Clearance and Synthesis Rates of Beta 2\u2010Microglobulin in Patients Undergoing Hemodialysis and in Normal Subjects","volume":"118","author":"Floege J.","year":"1991","journal-title":"Journal of Laboratory and Clinical 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