Hsp40/DnaJ is a family of proteins, established by bacterial DnaJ, that regulates Hsp70 chaperone activity. Hsp40s stimulate the intrinsically weak ATPase activity of Hsp70 proteins and facilitate Hsp70 interaction with polypeptide substrates. Hsp70 family members often have multiple Hsp40 partners, and these specific pairings govern Hsp70 chaperone involvement in particular processes (reviewed in 9, 10, and 11). All Hsp40s contain a highly conserved 75-amino acid J domain, which interacts with the ATPase domain of Hsp70 to stimulate ATP hydrolysis. However, there are also other conserved structural domains, and based on the presence or absence of these regions, the Hsp40 family can be divided into three subtypes: type I, type II and type III (a comprehensive overview of the structural features of the different HSP40 subtypes can be found in 11). Sequence analysis of the S. cerevisiae genome has revealed 22 proteins in the Hsp40/DnaJ family: YDJ1, XDJ1, APJ1, SIS1, DJP1, ZUO1, SWA2, JJJ1, JJJ2, JJJ3, CAJ1, CWC23, MDJ1, MDJ2, PAM18, JAC1, JID1, SCJ1, HLJ1, JEM1, SEC63, and ERJ5 (11).

Ydj1p is the regulating partner for the cytosolic Hsp70s Ssa1p and Ssa2p (and presumably the paralogs Ssa3p and Ssa4p) (12, 13). As an Ssa co-chaperone, Ydj1p is involved in the processes of cellular stress response, protein folding and re-folding (14, 15), suppression and rescue of protein aggregates (16, 17), mitochondrial and ER protein translocation (1, 5), establishment of Hsp90-mediated signal transduction pathways (3), and ubquitin-dependent degradation (18).

Loss of Ydj1p function results in defective mating, alpha-factor secretion, and inability to properly fold a heterologously expressed human androgen receptor protein (19, 20). Null mutations in ydj1 lead to a slow growth phenotype at 25 degrees C on solid media, and lethality in cells grown at 37 degrees C or in liquid culture (20, 1). This temperature-sensitive phenotype can be complemented by heterologous expression of either plant ANJ1, trypanosome TCJ2, or rat RDJ1 (21, 22, 23). YDJ1 overexpression has been studied in yeast models of human prion disease such as Creutzfeldt-Jakob disease (OMIM) and has been found to cure cells propagating the [PSI+] and [URE3] prions (isoforms of Sup35p and Ure2p, respectively) (24, 25, 26).

Comparative, mutational, and crystal structure analyses show that Ydj1p contains all of the structurally defined domains found in bacterial DnaJ, human Hdj2 (OMIM) and other type I Hsp40 proteins: an amino-terminal J domain linked by a glycine and phenylalanine-rich region to a zinc finger-like region (ZFLR) followed by a conserved carboxyl-terminal domain (1, 15, 20, 27, 11). Like other type I and type II Hsp40s, Ydj1p functions as a homodimer with protein dimerization being mediated by the Ydj1p C-terminus (28). The Ydj1p ZFLR has been shown to be required for substrate transfer to Hsp70 (20). Ydj1p is also a target for farnesylation, a modification that is necessary for the protein to function at elevated temperatures (29).

Last updated: 2006-12-19