biostudies-literatureDomanski PNational Science Center, Polande2522403123https://www.ebi.ac.uk/biostudies/studies/S-EPMC12799103biostudies-literatureUnknown123(2)J-domain protein (JDP) chaperones function widely in proteostasis. Notably, eukaryotic class B JDPs of the cytosol/nucleus prevent assembly or drive disassembly of amyloid aggregates known to cause neurodegenerative diseases, yet their evolutionary origin is not known. Members of the most ubiquitous class B subgroup, canonical B (B^C) JDPs, lack the signature zinc finger domain (ZnF) of the more prevalent class A JDPs, while having other key features in common. Our phylogenetic analysis revealed that B^C JDPs evolved more than once from class A duplicates, losing their ZnF. The cytonuclear B^Cs emerged at the base of eukaryotes. Cytonuclear class B' (i.e., B'^(ST)) JDPs that have a substrate binding domain of unknown origin, distinct from that of As Proceedings of the National Academy of Sciences of the United States of AmericaOrigin of class B J-domain proteins involved in amyloid transactions.PMC12799103OPUS 27; 2024/53/B/NZ1/00632OPUS 21 2021/41/B/NZ8/02835Bury KStolarska MSchilke BACzub JPurzycki DDomanski PWyszkowski HSzymanska AKlosowska AATomiczek BKalinowska KMarszalek JCraig EAPitek MfalseOrigin of class B J-domain proteins involved in amyloid transactions.J-domain protein (JDP) chaperones function widely in proteostasis. Notably, eukaryotic class B JDPs of the cytosol/nucleus prevent assembly or drive disassembly of amyloid aggregates known to cause neurodegenerative diseases, yet their evolutionary origin is not known. Members of the most ubiquitous class B subgroup, canonical B (B^C) JDPs, lack the signature zinc finger domain (ZnF) of the more prevalent class A JDPs, while having other key features in common. Our phylogenetic analysis revealed that B^C JDPs evolved more than once from class A duplicates, losing their ZnF. The cytonuclear B^Cs emerged at the base of eukaryotes. Cytonuclear class B' (i.e., B'^(ST)) JDPs that have a substrate binding domain of unknown origin, distinct from that of As 2026-01-01T00:00:00Z2026 Jan2026-07-15T13:32:43.697Z2026-07-05T03:08:42.336ZS-EPMC127991034151201710.1073/pnas.2522403123