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^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 and B^Cs, 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.