HSP40: Family Members7, 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.