Origin of class B J-domain proteins involved in amyloid transactions

Abstract

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 C s 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 and B C s, emerged from a B C duplication at the base of metazoans and subsequently multiplied by duplications. The origin of B’ (ST) s, which are capable of suppressing formation of amyloid aggregates, predated the emergence of disease-causing amyloidogenic proteins. Using ancestral protein resurrection, we tested when cytonuclear Bs evolved their amyloid related functions. We found that their common ancestor with As, AncAB that has a ZnF does not efficiently facilitate disassembly of amyloid fibrils, while AncB, which lacks a ZnF, does. Overall, our findings are consistent with the idea that, though the ZnF of class A JDPs is important for some roles, its loss allowed evolution of novel functions, as illustrated by the ability of B C and B’ (ST) JDPs to control amyloid aggregate levels.