Where Did Proteins That Tackle Disease-causing Amyloid Aggregates Come From?

What is it about?

Across prokaryotes and eukaryotes, J-domain proteins (JDPs) are key players in Hsp70 chaperone systems that maintain cellular protein homeostasis. The abundant class A and B JDPs have structural similarities, yet their origin has remained unresolved. Here, we show that B JDPs independently evolved from As more than once. In each case, A lost its zinc finger domain (ZnF), suggesting that such loss allowed evolution of new functions. Supporting this idea, biochemical resurrection of an ancestral eukaryotic B revealed that its ability to disassemble amyloid aggregates, differentiating it from As, evolved after ZnF loss. Later, the subset of Bs implicated in suppression of disease-causing amyloid aggregate formation originated from a duplicate of this B in an ancestor of animals.

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Photo by Robina Weermeijer on Unsplash

Photo by Robina Weermeijer on Unsplash

Why is it important?

This work holds profound importance for two main reasons: it resolves a fundamental evolutionary question in cellular biology and provides crucial insights into our efforts to combat devastating neurodegenerative diseases. The study demonstrates that Class B J-domain proteins (JDPs) evolved from Class A JDPs more than once. This evolutionary innovation was consistently propelled by the loss of a specific structural element, the zinc finger domain (ZnF), suggesting that such loss allowed the evolution of new functions. Crucially, this research directly links these evolutionary changes to the cell's capacity to combat harmful protein aggregates, known as amyloids, which are hallmarks of neurodegenerative conditions like Alzheimer's. By revealing when and how these specialized JDPs developed their capacity to disaggregate amyloids, even predating the emergence of some disease-causing amyloidogenic proteins, the study uncovers the molecular origins of the cell's inherent defenses against these debilitating diseases. Understanding this evolutionary history and the precise mechanisms involved offers invaluable mechanistic insights that can guide future therapeutic strategies aimed at bolstering our cellular machinery to prevent or treat protein aggregation disorders.