{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T19:09:19Z","timestamp":1771614559955,"version":"3.50.1"},"reference-count":63,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,11,17]],"date-time":"2021-11-17T00:00:00Z","timestamp":1637107200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research, Development, and Innovation Fund, Hungary","award":["2017-1.2.1-NKP-2017-00002, K120391, K138937, 2019-2.1.11-T\u00c9T-2019-00079, 2018-2.1.17-T\u00c9T-KR-2018-00008, PD135510"],"award-info":[{"award-number":["2017-1.2.1-NKP-2017-00002, K120391, K138937, 2019-2.1.11-T\u00c9T-2019-00079, 2018-2.1.17-T\u00c9T-KR-2018-00008, PD135510"]}]},{"name":"Bolyai J\u00e1nos Scholarship of the Hungarian Academy of Sciences","award":["for A.M."],"award-info":[{"award-number":["for A.M."]}]},{"name":"New National Excellence Program","award":["\u00daNKP-18-4-ELTE-833"],"award-info":[{"award-number":["\u00daNKP-18-4-ELTE-833"]}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2019R1A2C1004954"],"award-info":[{"award-number":["2019R1A2C1004954"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003716","name":"Korea Basic Science Institute","doi-asserted-by":"publisher","award":["C130000, C180310, C140130, and C17010"],"award-info":[{"award-number":["C130000, C180310, C140130, and C17010"]}],"id":[{"id":"10.13039\/501100003716","id-type":"DOI","asserted-by":"publisher"}]},{"name":"E\u00f6tv\u00f6s Lor\u00e1nd Research Network","award":["0106307"],"award-info":[{"award-number":["0106307"]}]},{"name":"Institutional Excellence Program to ELTE","award":["NKFIH-1157\/8\/2019, D11206"],"award-info":[{"award-number":["NKFIH-1157\/8\/2019, D11206"]}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["Core-to-Core Program A (Advance Research Networks)"],"award-info":[{"award-number":["Core-to-Core Program A (Advance Research Networks)"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>\u03b22-microglobulin (\u03b22m), the light chain of the MHC-I complex, is associated with dialysis-related amyloidosis (DRA). Recently, a hereditary systemic amyloidosis was discovered, caused by a naturally occurring D76N \u03b22m variant, which showed a structure remarkably similar to the wild-type (WT) protein, albeit with decreased thermodynamic stability and increased amyloidogenicity. Here, we investigated the role of the D76N mutation in the amyloid formation of \u03b22m by point mutations affecting the Asp76-Lys41 ion-pair of WT \u03b22m and the charge cluster on Asp38. Using a variety of biophysical techniques, we investigated the conformational stability and partial unfolding of the native state of the variants, as well as their amyloidogenic propensity and the stability of amyloid fibrils under various conditions. Furthermore, we studied the intermolecular interactions of WT and mutant proteins with various binding partners that might have in vivo relevance. We found that, relative to WT \u03b22m, the exceptional amyloidogenicity of the pathogenic D76N \u03b22m variant is realized by the deleterious synergy of diverse effects of destabilized native structure, higher sensitivity to negatively charged amphiphilic molecules (e.g., lipids) and polyphosphate, more effective fibril nucleation, higher conformational stability of fibrils, and elevated affinity for extracellular components, including extracellular matrix proteins.<\/jats:p>","DOI":"10.3390\/biology10111197","type":"journal-article","created":{"date-parts":[[2021,11,17]],"date-time":"2021-11-17T21:32:07Z","timestamp":1637184727000},"page":"1197","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Pathogenic D76N Variant of \u03b22-Microglobulin: Synergy of Diverse Effects in Both the Native and Amyloid States"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3119-8059","authenticated-orcid":false,"given":"\u00c9va","family":"Buly\u00e1ki","sequence":"first","affiliation":[{"name":"ELTE NAP Neuroimmunology Research Group, Department of Biochemistry, Institute of Biology, ELTE E\u00f6tv\u00f6s Lor\u00e1nd University, 1117 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9886-4426","authenticated-orcid":false,"given":"Judit","family":"Kun","sequence":"additional","affiliation":[{"name":"ELTE NAP Neuroimmunology Research Group, Department of Biochemistry, Institute of Biology, ELTE E\u00f6tv\u00f6s Lor\u00e1nd University, 1117 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tam\u00e1s","family":"Moln\u00e1r","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Institute of Biology, ELTE E\u00f6tv\u00f6s Lor\u00e1nd University, 1117 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandra","family":"Papp","sequence":"additional","affiliation":[{"name":"Complement Research Group, Department of Immunology, ELTE E\u00f6tv\u00f6s Lor\u00e1nd University, 1117 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andr\u00e1s","family":"Micsonai","sequence":"additional","affiliation":[{"name":"ELTE NAP Neuroimmunology Research Group, Department of Biochemistry, Institute of Biology, ELTE E\u00f6tv\u00f6s Lor\u00e1nd University, 1117 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henrietta","family":"Vad\u00e1szi","sequence":"additional","affiliation":[{"name":"ELTE NAP Neuroimmunology Research Group, Department of Biochemistry, Institute of Biology, ELTE E\u00f6tv\u00f6s Lor\u00e1nd University, 1117 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Borb\u00e1la","family":"M\u00e1rialigeti","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Institute of Biology, ELTE E\u00f6tv\u00f6s Lor\u00e1nd University, 1117 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Attila Istv\u00e1n","family":"Kov\u00e1cs","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Institute of Biology, ELTE E\u00f6tv\u00f6s Lor\u00e1nd University, 1117 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9048-2722","authenticated-orcid":false,"given":"Gabriella","family":"Gell\u00e9n","sequence":"additional","affiliation":[{"name":"Department of Analytical Chemistry, Institute of Chemistry, ELTE E\u00f6tv\u00f6s Lor\u00e1nd University, 1117 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keiichi","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Global Center for Medical Engineering and Informatics, Osaka University, Osaka 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuxi","family":"Lin","sequence":"additional","affiliation":[{"name":"Research Center of Bioconvergence Analysis, Korea Basic Science Institute (KBSI), Ochang 28119, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4815-4995","authenticated-orcid":false,"given":"Masatomo","family":"So","sequence":"additional","affiliation":[{"name":"Institute for Protein Research, Osaka University, Osaka 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5520-5535","authenticated-orcid":false,"given":"Mih\u00e1ly","family":"J\u00f3zsi","sequence":"additional","affiliation":[{"name":"Complement Research Group, Department of Immunology, ELTE E\u00f6tv\u00f6s Lor\u00e1nd University, 1117 Budapest, Hungary"},{"name":"MTA-ELTE Complement Research Group, E\u00f6tv\u00f6s Lor\u00e1nd Research Network (ELKH), Department of Immunology, ELTE E\u00f6tv\u00f6s Lor\u00e1nd University, 1117 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7637-7133","authenticated-orcid":false,"given":"Gitta","family":"Schlosser","sequence":"additional","affiliation":[{"name":"Department of Analytical Chemistry, Institute of Chemistry, ELTE E\u00f6tv\u00f6s Lor\u00e1nd University, 1117 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Young-Ho","family":"Lee","sequence":"additional","affiliation":[{"name":"Research Center of Bioconvergence Analysis, Korea Basic Science Institute (KBSI), Ochang 28119, Korea"},{"name":"Bio-Analytical Science, University of Science and Technology (UST), Daejeon 34113, Korea"},{"name":"Graduate School of Analytical Science and Technology (GRAST), Chungnam National University (CNU), Daejeon 34134, Korea"},{"name":"Research Headquarters, Korea Brain Research Institute (KBRI), Daegu 41068, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7177-6872","authenticated-orcid":false,"given":"K\u00e1roly","family":"Liliom","sequence":"additional","affiliation":[{"name":"Department of Biophysics and Radiation Biology, Faculty of Medicine, Semmelweis University, 1094 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1221-1270","authenticated-orcid":false,"given":"Yuji","family":"Goto","sequence":"additional","affiliation":[{"name":"Global Center for Medical Engineering and Informatics, Osaka University, Osaka 565-0871, Japan"},{"name":"Institute for Protein Research, Osaka University, Osaka 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2135-2932","authenticated-orcid":false,"given":"J\u00f3zsef","family":"Kardos","sequence":"additional","affiliation":[{"name":"ELTE NAP Neuroimmunology Research Group, Department of Biochemistry, Institute of Biology, ELTE E\u00f6tv\u00f6s Lor\u00e1nd University, 1117 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1016\/j.cell.2012.02.022","article-title":"The amyloid state of proteins in human diseases","volume":"148","author":"Eisenberg","year":"2012","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1098\/rstb.2000.0766","article-title":"Pathogenesis, diagnosis and treatment of systemic amyloidosis","volume":"356","author":"Pepys","year":"2001","journal-title":"Philos. 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