Characterization of the interaction between Hsp70s and lipids: evolutionary and functional implications

Abstract

Hsp70s are molecular chaperones indispensable for cellular homeostasis under both normal and pathological conditions. Apart from their associations with protein substrates, Hsp70s also associate with membrane lipids. This association has been related to their membrane localization and anchorage, secretion and endocytosis, as well as their functions in stabilizing membranes and cell signaling. Despite the essential role of membrane‐associated Hsp70s in cell survival, their interactions with membranes and lipids, as well as the effect that lipid‐binding has on their chaperone activities remain unknown. To this end, we determined that several eukaryotic and prokaryotic Hsp70s bind to phospholipids with different affinities suggesting that Hsp70s are functionally differentiated with respect to their lipid‐binding properties. We next established that the nucleotide binding domain of Hsp70s contains multiple lipid‐binding sites, a result that was also supported by mutagenesis experiments, which further identified critical residues for different lipids. Furthermore, we determined that lipid‐binding significantly reduces the refolding activity of Hsp70s, suggesting a new regulatory mechanism of chaperone function. Collectively, these results provide fundamental knowledge towards understanding the full spectrum of biologically significant activities mediated by Hsp70‐lipid interactions.This project was supported by funds from CSUPERB and CSUF to NN.