DNAJ

DNAJ refers to a large and diverse family of molecular chaperones that function as the primary co-chaperones of Hsp70 proteins (Hsp40). Members of the DNAJ family assist in protein folding, refolding of misfolded proteins, translocation across membranes, and targeting proteins for degradation. The family is widespread, with bacterial DnaJ, and numerous homologs in plants, fungi, and animals, all contributing to cellular proteostasis.

A hallmark of DNAJ proteins is a conserved N-terminal J-domain that contains the histidine-proline-aspartate (HPD) motif, essential for stimulating Hsp70 ATPase activity. Based on additional domains, DNAJs are commonly classified into three major classes. Type I proteins have the J-domain, a glycine/phenylalanine-rich region, a zinc-finger Cys-rich domain, and a C-terminal substrate-binding region. Type II proteins lack the zinc-finger region but retain the J-domain and G/F region. Type III proteins contain only the J-domain with little or no other conserved regions. In eukaryotes, many DNAJs include targeting signals that direct them to mitochondria, the endoplasmic reticulum, or other cellular compartments; their C-terminal regions often determine substrate specificity.

Functionally, DNAJs recruit substrate proteins to Hsp70 and regulate the ATPase cycle to promote efficient binding and release of clients. The J-domain stimulates Hsp70 activity, while DNAJ-specific regions recognize and present unfolded or partially folded proteins to Hsp70. The family comprises numerous paralogs, enabling tailored chaperone support across cellular contexts, including protein import into organelles, assembly of protein complexes, stress responses, and degradation pathways such as ER-associated degradation.

Dysfunction or mutation of certain DNAJs has been linked to neurodegenerative diseases and cancer, highlighting their critical role in maintaining proteome integrity.