{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T22:29:34Z","timestamp":1787005774576,"version":"build-2736575974"},"reference-count":47,"publisher":"National Academy of Sciences","issue":"18","license":[{"start":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T00:00:00Z","timestamp":1746144000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010434","name":"'la Caixa' Foundation","doi-asserted-by":"publisher","award":["LCF\/PR\/HR21\/52410004"],"award-info":[{"award-number":["LCF\/PR\/HR21\/52410004"]}],"id":[{"id":"10.13039\/100010434","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["RYC2020-028861-I"],"award-info":[{"award-number":["RYC2020-028861-I"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["101125484"],"award-info":[{"award-number":["101125484"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,5,6]]},"abstract":"<jats:p>\n                    Stop-loss mutations cause over twenty different diseases. The effects of stop-loss mutations can have multiple consequences that are, however, hard to predict. Stop-loss in\n                    <jats:italic>ITM2B\/BRI2<\/jats:italic>\n                    results in C-terminal extension of the encoded protein and, upon furin cleavage, in the production of two 34 amino acid long peptides, ADan and ABri, that accumulate as amyloids in the brains of patients affected by familial Danish and British Dementia. To systematically explore the consequences of Bri2 C-terminal extension, here, we use a yeast-based massively parallel assay to measure amyloid formation for 676 ADan substitutions and identify the region that forms the putative amyloid core of ADan fibrils, located between positions 20 and 26, where stop-loss occurs. Moreover, we measure amyloid formation for ~18,000 random C-terminal extensions of Bri2 and find that ~32% of these sequences can nucleate amyloids. We find that the amino acid composition of these nucleating sequences varies with peptide length and that short extensions of two specific amino acids (Aliphatics, Aromatics, and Cysteines) are sufficient to generate de novo amyloid cores. Overall, our results show that the C-terminus of Bri2 contains an incomplete amyloid motif that can turn amyloidogenic upon extension. C-terminal extension with de novo formation of amyloid motifs may thus be a widespread pathogenic mechanism resulting from stop-loss, highlighting the importance of determining the impact of these mutations for other sequences across the genome.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2415521122","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T11:35:49Z","timestamp":1746185749000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":3,"title":["Massive mutagenesis reveals an incomplete amyloid motif in Bri2 that turns amyloidogenic upon C-terminal extension"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9518-2630","authenticated-orcid":false,"given":"Mariano","family":"Mart\u00edn","sequence":"first","affiliation":[{"name":"Institute for Bioengineering of Catalonia, The Barcelona Institute of Science and Technology","place":["Barcelona, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6632-947X","authenticated-orcid":false,"given":"Benedetta","family":"Bolognesi","sequence":"additional","affiliation":[{"name":"Institute for Bioengineering of Catalonia, The Barcelona Institute of Science and Technology","place":["Barcelona, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,5,2]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1186\/1479-7364-5-4-241"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2023114378"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa136"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature18308"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-020-0551-7"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.670901"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/jhg.2017.30"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.495184"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.02.022"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/21637"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23369"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.080076097"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-230051"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-210176"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M117.809004"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.63364"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2015.10.003"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2006.01.011"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2023.1070521"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.563981"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-34742-3"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06045-0"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2205500119"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.7754373"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63993-4"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M105956200"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2990.2006.00747.x"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac240"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2836(82)90515-0"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/bip.1980.360190906"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.2008.00164.x"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.2006.tb00564.x"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-9-5"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.049510"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2022.101941"},{"key":"e_1_3_4_36_2","doi-asserted-by":"crossref","unstructured":"M. Thompson Massive experimental quantification of amyloid nucleation allows interpretable deep learning of protein aggregation. bioRxiv [Preprint] (2024). https:\/\/doi.org\/10.1101\/2024.07.13.603366 (Accessed 1 October 2024).","DOI":"10.1101\/2024.07.13.603366"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1002608"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1080\/15476286.2015.1068497"},{"key":"e_1_3_4_39_2","doi-asserted-by":"crossref","unstructured":"I. Toledano F. Supek B. Lehner Genome-scale quantification and prediction of pathogenic stop codon readthrough by small molecules. Nat. Genet. 56 1914\u20131924 (2024).","DOI":"10.1038\/s41588-024-01878-5"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1002\/yea.1142"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-020-02091-3"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1012"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-11897-z"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2014.09.026"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-8-65"},{"key":"e_1_3_4_46_2","unstructured":"M. Mart\u00edn B. Bolognesi Deep mutagenesis reveals the distinct mutational landscape of ADan and ABri amyloid nucleation. Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE244612. Deposited 9 October 2023."},{"key":"e_1_3_4_47_2","doi-asserted-by":"crossref","unstructured":"M. Mart\u00edn B. Bolognesi Amyloids \u201cat the border\u201d: Deep mutagenesis and random sequence extension reveal an incomplete amyloid-forming motif in Bri2 that turns amyloidogenic upon C-terminal extension. Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE270792. 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