Hsp70 diversification and repurposing across the tree of life: Lessons from the evolutionary and mechanistic trajectory of the Hsp70-Hsp110 chaperone system.

The 70 kDa Heat Shock Proteins (Hsp70s) are molecular chaperones ubiquitous in most free-living bacteria and archaea, and in the cytosol and ATP-containing organelles of eukaryotic cells, where they act as ATP-fueled nanomachines that unfold, remodel, and translocate polypeptides. In bacteria, Hsp70 (DnaK) operates with the J-domain cochaperone DnaJ and the nucleotide exchange factor (NEF) GrpE, which accelerates ADP release and ATP rebinding. Many simple prokaryotes encode a single canonical DnaK, but more complex bacteria often harbor additional DnaK-derived paralogues with modified, truncated, or missing domains required for substrate and DnaJ binding, raising questions about their functions and possible roles in proteostasis. A suggestive parallel comes from eukaryogenesis, when a gene duplication of an ancestral Hsp70 gave rise to Hsp110. Hsp110s have largely abandoned direct DnaJ, GrpE, and substrate binding; yet, through the reversible formation of NBD-mediated Hsp70-Hsp110 heterodimers, they act as potent NEFs that enhance Hsp70-driven disaggregation of compact protein aggregates. By analogy, we propose that NBD-containing DnaK paralogues in prokaryotes may likewise function as dedicated DnaK cochaperones, tuned to boost protein disaggregation and repair and specialized for the specific lifestyles and associated stressors of these organisms.