Hsp40

Hsp40, also known as DnaJ or J-domain protein (JDP), is a family of molecular chaperones that function as co-chaperones of Hsp70 chaperones. They regulate protein folding, trafficking, and degradation by delivering substrates to Hsp70 and stimulating its ATPase activity.

Most Hsp40s share a conserved J-domain containing the HPD motif, which interacts with Hsp70. Based on domain organization, JDPs are grouped into three classes: Class I proteins have an N-terminal J-domain, a glycine/phenylalanine-rich G/F region, and a C-terminal substrate-binding domain; Class II proteins resemble Class I but lack the zinc-binding zinc finger region; Class III proteins contain only a J-domain linked to diverse additional regions and substrates. In eukaryotes, these correspond to DNAJA, DNAJB, and DNAJC families, respectively.

Functions of Hsp40 proteins include assisting in the folding of nascent polypeptides, refolding of stress-denatured proteins, assembly of multi-subunit complexes, translocation across membranes, and targeting misfolded proteins to degradation pathways. They recruit Hsp70 to client proteins, prevent aggregation, and, in some cases, cooperate with nucleotide-exchange factors to regulate substrate release.

Localization and significance: Hsp40 proteins are found in the cytosol, mitochondria, and the endoplasmic reticulum, including ER-resident members of the DNAJC family that support protein import and quality control in the secretory pathway. Because they are central to proteostasis, Hsp40/Hsp70 systems are connected to aging and diseases involving protein misfolding, such as neurodegenerative disorders and cancer.

Notable human members include DNAJA1 (Hsp40/Hdj2), DNAJB1 (Hsp40/Hdj1), and DNAJC3 (p58IPK).