HSP40: Family Members

The 40 kDa chaperone family of proteins (HSP40, DNAJ) consists of molecular chaperones of approximately 40 kDa in size comprising stress inducible and constitutively expressed members ^{7, 8, 63, 64}. Historically, HSP40s/DNAJs have been classified into three subtypes (1, 2 and 3; also referred as to subfamily A, B, and C; Figure 1 ^33,34,35). Type 1 DNAJs/HSP40s consist of at least four conserved domains similar to the domain structure of E. coli DnaJ: an N-terminal J-domain followed by a Gly/Phe (G/F)-rich region, a central Cys-rich region consisting of four repeats of the ZF motif CXXCXGXG, and a C-terminal region involved in binding of client proteins ^{48, 65, 66}. Moreover, the extreme C-terminus possesses a dimerization domain which functions in enhancing affinity for client proteins ⁶⁷. In contrast, proteins lacking the ZF motifs are classified as type 2 members while type 3 proteins only have the J-domain not necessarily located at the N-terminus. This historical classification does not relate to the function or effectiveness of members in a particular subtype because several functional and structural diversities exist ⁷. However, DNAJs/HSP40s whose domain structures do not match those found in subtype 1 or subtype 2 have also been denoted as type 3.

A large number of DnaJ/Hsp40 homologs have been identified in pro- and eukaryotes. While E. coli expresses six DnaJ/Hsp40 homologs, in S. cerevisiae 22 DnaJ/Hsp40 homologs with well-conserved J-domains can be found (Table 2) ¹⁰. In the S. cerevisiae genome, five DnaJ/Hsp40 homologs have been classified as type 1, four as type 2, and 13 as type 3 HSP40/DNAJ ^{10, 68}. The HSP40/DNAJ family represents the largest HSP family in humans comprising 50 family members, even though the exact number is still unclear ⁸. According to Kampinga and colleagues, the human genome encodes four type 1, 14 type 2 as well as 23 type 3 DNAJ/HSP40 proteins and nine J-like proteins (Table 2) ⁶³. The human genome possesses many DNAJ pseudogenes lacking major parts of the coding sequence and showing only partial homology to DNAJ. In addition, three J-like proteins were identified in yeast that contain regions closely resembling a J-domain, but in which the HPD motif is non-conservatively replaced ¹⁰. Genome-wide analysis revealed seven HSP40/DNAJ proteins bearing partially conserved J-like domains in humans ⁸. Amongst them, DnaJB13/Tsarg- 6 has the HPL tripeptide in place of the HPD motif which plays a crucial role in J-domain functions. DnaJB10 is actually the mouse ortholog of human DnaJB2 and therefore missing amongst the human HSP40/DNAJ family members. A detailed description of pro- and eukaryotic DNAJ/HSP40 family members is given in Table 2 and the Isoforms section.