Inherent chaperone‐like activity of aspartic proteases reveals a distant evolutionary relation to double‐ψ barrel domains of AAA‐ATPases

Abstract Chaperones and proteases share the ability to interact with unfolded proteins. Here we show that enzymatically inactive forms of the aspartic proteases HIV‐1 protease and pepsin have inherent chaperone‐like activity and can prevent the aggregation of denatured substrate proteins. In contrast to proteolysis, which requires dimeric enzymes, chaperone‐like activity could be observed also with monomeric domains. The involvement of the active site cleft in the chaperone‐like function was demonstrated by the inhibitory effect of peptide substrate inhibitors. The high structural similarity between aspartic proteases and the N‐terminal double‐ψ barrels of Cdc48‐like proteins, which are involved in the unfolding and dissociation of proteins, suggests that they share a common ancestor. The latent chaperone‐like activity in aspartic proteases can be seen as a relic that has further evolved to serve substrate binding in the context of proteolytic activity.