DNAJHsp40

DnaJ, also known as Hsp40, refers to a large and conserved family of molecular co-chaperones that regulate Hsp70 activity. Members of the DnaJ/Hsp40 family are found in bacteria, archaea, and eukaryotes, and they play essential roles in protein folding, refolding of stress-denatured proteins, and prevention of aggregation.

Most DnaJ proteins share a common J-domain at the N-terminus, which interacts with Hsp70 to stimulate its ATPase activity. Additional regions confer substrate binding and specificity. Based on domain composition, DnaJ family proteins are typically classified as type I (J-domain, glycine/phenylalanine-rich region, zinc-finger–like Cys-rich domain, and a C-terminal client-binding domain), type II (J-domain, G/F region, but lacking the zinc finger domain), or type III (only the J-domain with variable flanking regions).

In operation, the J-domain accelerates the conversion of Hsp70 to a high-affinity state for unfolded proteins, while the substrate-binding region of the DnaJ partner delivers client polypeptides to Hsp70 for folding, stabilization, or degradation. The two proteins function as a dynamic chaperone system, often alongside other cochaperones and proteostasis factors.

Localization varies by member: bacterial DnaJ is typically cytosolic, while eukaryotic DnaJ proteins (DNAJA, DNAJB, DNAJC families) can be cytosolic, mitochondrial, endoplasmic reticulum–associated, or nuclear, reflecting specialized roles in cellular compartments.

DnaJ/Hsp40 proteins are central to maintaining proteome homeostasis, especially under stress. They participate in development, signaling, and response to proteotoxic stress. Dysfunctions in specific DnaJ/Hsp40 proteins have been linked to neurodegenerative diseases and cancer in humans.