HSP40: Species Variation

The DNAJ/HSP40 protein family is composed of six homologs in E. coli ⁶. Higher organisms express many more of these proteins. There are at least 43 Hsp40/DnaJ homologs in Plasmodium falciparum ⁹⁸, 22 homologs in the yeast S. cerevisiae, and 50 homologs in humans ⁶³. Almost 50% of DNAJs/HSP40s in P. falciparum have been second-guessed to bear a Plasmodium export element/host targeting motif at the N-terminus critical for the export and thus are likely to be part of the “exportome” ⁹⁹. Comparison of the DNAJ/HSP40 proteins of P. falciparum to those of other apicomplexa by Botha and co-workers revealed that most of these molecules are unique to P. falciparum ⁹⁸. Moreover, only a small number of P. falciparum DNAJs/HSP40s have human homologs, except for those proteins implicated in basic biological processes. From these findings it can be concluded that P. falciparum has evolved an expanded and specialized DNAJ/HSP40 machinery to efficiently invade and remodel human red blood cells ⁹⁸. Apart from the classical type 1, 2, and 3 DNAJ/HSP40 proteins, P. falciparum expresses a number of specialized DNAJs/HSP40s with a J-like domain, all of which being part of a protein interaction network associated with cytoskeletal and membrane proteins, transcriptional machinery, DNA repair and replication machinery, translational machinery, the proteasome and proteolytic enzymes, and enzymes involved in cellular physiology ⁹⁸.

Genes for Hsp40/DnaJ homologs are only found in a subset of Archaea including Halobacterium spec., Methanosarcina spec., and Methanobacterium spec. ¹⁰⁰. Archeal DNAJs/HSP40s are expressed by at least four dnaJ genes (for a review see Macario et al., 1999 ¹⁰⁰). Archaeal DNAJs/HSP40s show a high similarity to each other and to their bacterial homologs with the most similar pair represented by the two DNAJ/HSP40 proteins found in Methanosarcina (Table 2). In Halobacterium cutirubrum, the G/F-rich domain in DnaJ is longer with a larger number of Gly residues compared to those of the other DNAJs/HSP40s from methanogens ¹⁰⁰. In addition, H. cutirubrum DnaJ shows a different arrangement of the four repeats of the conserved CXXCXGXG motif compared to the molecules in the methanogens. It is worth mentioning that motif 1 is located closer to the C-terminus in H. cutirubrum DnaJ than in the others. As a consequence, the CXXCXGXG motif 4 in H. cutirubrum DnaJ is located much closer to the C-terminus than motif 4 in those from the methanogens ¹⁰⁰. Whether this phenomenon represents a unique feature of H. cutirubrum DnaJ in order to adapt to life under high-salinity conditions and/or to cope with salinity changes is still unclear.

The plant genomes of Arabidopsis thaliana and rice (Oryza sativa) encode approximately 90 and 104 DNAJ/HSP40 proteins, respectively ^{101, 102}. ERDJ genes encoding the ER-resident HSP40/DNAJ (also termed ERdj) proteins are present in different copy numbers in Arabidopsis and rice. While Arabidopsis has two copies of ERDJ2A (ATERDJ2A and ATERDJ2B) ¹⁰³, rice bears one copy, OSERDJ2 ¹⁰⁴. Rice has two P58IPK gene copies (OSP58A and OSP58B) ¹⁰⁴, whereas Arabidopsis has only one copy ¹⁰³. Expression of AtERdj2B is induced by ER stress, while AtERdj2A is constitutively expressed ¹⁰³. ER stress also differentially impacts rice Osp58A^IPK and Osp58B^IPK expression. Whereas Osp58A^IPK represents the constitutively expressed isoform, Osp58B^IPK is induced by ER stress implying diverse functions of duplicated genes encoding ER-resident DNAJs/HSP40s in different plants ¹⁰⁴.

The haploid genome of the green alga Chlamydomonas reinhardtii encodes 63 DNAJ/HSP40 proteins, with more than half of these localized to the cytosol, suggesting an interaction of various DNAJ/HSP40 proteins with single cytosolic HSP70s ^{105, 106}. However, only three DNAJs/HSP40s are type 1 proteins with ZF domains containing CXXCXGXG motifs. These proteins are targeted separately to the mitochondrial (Mdj1), plastidic (Cdj1), and cytosolic (Dnj1) compartments ¹⁰⁷. The DNJ1 gene contains an open reading frame interrupted by six introns encoding a protein of 450 amino acids ¹⁰⁸. The protein harbors the J-domain, the G/F-rich region as well as the C-rich ZF domain what classifies it as type 1 DNAJ/HSP40 protein. Phylogenetic studies revealed the most highly conserved homologs as cytosolic DNAJ/HSP40 proteins from plants ¹⁰⁷. Alignment of the Chlamydomonas protein with the plant proteins led to the identification of an N-terminal extension of 19 amino acids enriched in methionine, glycine, phenylalanine, and proline. Similar to the other DNAJ/HSP40 proteins from plants, Chlamydomonas Dnj1 contains a CAQQ motif at the C-terminus ^{109, 110}, indicating a putative post-translational modification by prenylation as has been reported in numerous plant DNAJs/HSP40s ¹¹¹ and for Ydj1 from S. cerevisiae ¹¹². As demonstrated by Silflow and colleagues, Dnj1 from Chlamydomonas obviously plays a critical role in regulating the stability of cytoplasmic microtubules in conjunction with Hsp70A (HspA1A) ¹⁰⁸.

Six DnaJ/Hsp40 homologs have been found in E. coli including the eponymous type 1 family member DnaJ (Table 2) ⁶. DnaJ is composed of 376 amino acid residues and functions as a chaperone with thioldisulfide oxidoreductase activity (Figure 1). As the defining feature, DnaJ possesses an N-terminal J-domain bearing the highly conserved tripeptide HPD critical for the interaction with Hsp70. Adjacent to the J-domain, DnaJ bears the G/F-rich region followed by 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. A small angle X-ray scattering study revealed that DnaJ is a distorted omega-shaped homodimeric molecule with the C-terminus of each subunit forming the central part of the omega ¹¹³. Dimerization occurs through the C-terminal residues (331-376) resulting in the formation of a large cleft constituted between the two DnaJ monomers ¹¹³. As stated by the authors, the interaction between the two subunits may occur in different ways: firstly, the 331–376 amino acid stretch from each of the subunits may interact with each other; and secondly, this stretch on each submit may interact with another part of the other subunit, as can be found in yeast Sis1 ¹¹⁴ and Ydj ⁶⁵, respectively. From these findings it can be concluded that the simultaneous binding of a non-native polypeptide to each monomer might ensure maintaining the transfer-competent form of the molecule ⁶.

In addition to DnaJ, E. coli contains five other DnaJ homologs, including CbpA (curved DNA-binding protein A), which was first identified as a DNA-binding protein ¹¹⁵. CbpA binds DNA efficiently, with a preference for curved DNA, and has been localized to the nucleoids of stationary-phase cells ^{115, 116}. DNA binding to CbpA has been found to depend on the presence of the G/F-rich as well as the C-terminal domain (CTD) crucially involved in binding of polypeptides ¹¹⁷. In recent years a wealth of evidence has been collected to demonstrate that CbpA functions as a co-chaperone of DnaK. In this regard, CbpA upregulation has been found to suppress several phenotypes associated with dnaJ deletions, including temperature sensitivity and λ replication defects ¹¹⁵. Any CbpA co-chaperone function is also blocked by DNA binding indicating a possible covering of the substrate binding site and impeding of the DnaK/DnaJ interaction ^{117, 118}. CbpA differs from DnaJ in that it is a type 2 DNAJ/HSP40 protein, lacking the ZF domain characteristic of E. coli DnaJ and other type 1 DNAJ/HSP40 proteins. Like DnaJ, CbpA forms homodimers in solution with dimerization occurring at the extreme C-terminus ^{117, 118}. In E. coli, the cbpA gene forms an operon together with the downstream gene cbpM encoding a CbpA modulator. Based on the fact that the corresponding proteins accumulate in the stationary phase, one can hypothesize that they are under control of the same σ^s-dependent promoter ¹¹⁸. This intriguing operon structure is conserved in numerous bacteria including Coxiella burnetii, Pseudomonas fluorescens, Salmonella enterica serovar Typhimurium, Shigella flexneri as well as in enterophila and putida.

DljA is a 30 kDa membrane-anchored type 3 DNAJ/HSP40 protein localized to the inner membrane of E. coli and characterized by the presence of the C-terminal J-domain and an N-terminal transmembrane domain (TMD) with dimerizing capacity ^{119,120,121,122}. It is interesting to note that the conserved Gly residues within the TMD are obviously not involved in dimerization of DljA ¹¹⁹.The DjlA J-domain shows 31% identity and 44% similarity to the J-domain of DnaJ, including the highly conserved HPD tripeptide ^{120, 123}. It is noteworthy that the J-domain of DjlA lacks the QKRAA motif which has been described as a possible interaction site with DnaK ^{123, 124}. Although DjlA possesses a functional J-domain, it cannot be considered as being a functional ortholog of DnaJ and CbpA. As demonstrated previously, DjlA is unable to adequately complement DnaJ function in a strain lacking both dnaJ and cbpA, even when expressed to the same levels of DnaJ ^{120, 121}. Overexpression of the DjlA cytoplasmic fragment could not support bacterial growth of the dnaJ/cbpA-deficient strain at temperatures below 20 °C and above 39 °C, respectively ^{120, 121}. Additionally, DjlA has been found in these studies as being unable to replace either DnaJ or CbpA in promoting bacteriophage λ growth. DjlA is classified as a bona fide co-chaperone of DnaK, although it does not apparently possess intrinsic chaperone activity alone as can be found in DnaJ ¹²⁵. Of note, the djlA gene is not essential and a single djlA mutant does not have a distinguishable phenotypic effect ¹²³. As demonstrated previously, djlA and dnaJ obviously interact synergistically in supporting growth of E. coli ¹²³. A growing body of evidence now indicates the expression of genes with sequence similarities to E. coli djlA in a broad spectrum of Gram-negative bacteria such as Legionella spec., S. flexneri, Shewanella putrefacians, S. typhimurium, Vibrio cholerae, C. burnetii, Haemophilus influenzae as well as Yersinia pestis and Y. entercolitica ⁶. Expression of DjlA has been reported recently as being a prerequisite for intracellular growth and organelle trafficking as well as resistance to environmental stress in L. dumoffii, one of the common causes of Legionnaires’ disease ¹²⁶.

E. coli further expresses the djlB and djlC genes encoding two type 3 DNAJs/HSP40s ¹²⁷. These proteins exhibit an amino acid sequence similarity of ≈70% and bear an N-terminal J-domain as well as a putative C-terminal TMD. Due to the high homlogy of DjlB and DjlC, these DNAJs/HSP40s can be considered as being bona fide co-chaperones of HscC/Hsc62 in E. coli. A characteristic structural feature of J-domains is the presence of the highly conserved tripeptide HPD critical for the interaction with Hsp70. It is noteworthy that DjlB and DjlC possess an HPE motif in place of the canonical HPD motif in their particular J-domains ⁶. In this regard, HscC/Hsc62 represents a rare example of an Hsp70 chaperone interacting with a J domain-bearing co-chaperone lacking the conserved HPD tripeptide. Functionally, DjlC has been reported to stimulate the ATPase activity of HscC/Hsc62 while CbpA, DnaJ, and HscB/Hsc20 do not ¹²⁸.

HscB, also known as Hsc20, is a 20 kDa monomeric type 3 DNAJ/HSP40 protein that regulates the ATPase activity and peptide-binding specificity of HscA/Hsc66 in E.coli ⁵⁶. HscB bears an N-terminal J-domain resembling the J-domain of human DnaJB1/Hdj1 and showing 20% identity to the J-domain of DnaJ ^{6, 56}. Unlike the CTD found in type 1 DNAJs/HSP40s, the C-terminal region of HscB/Hsc20, implicated in binding and targeting proteins to DnaJB1/Hsc66, consists of a three-helix bundle in which two helices comprise an anti-parallel coiled-coil ⁵⁶. Moreover, HscB/Hsc20, unlike DnaJ, does not possess intrinsic chaperone activity and appears to function solely as a regulatory co-chaperone protein for DnaJB1/Hsc66 ¹²⁹. HscB/Hsc20 also plays a critical role in the assembly of [Fe-S] proteins. The group of Larry E. Vickery found out that HscB/Hsc20 interacts with the ATP-bound state of the [Fe-S] cluster scaffold protein IscU, an essential component of the [Fe-S] cluster biogenesis pathway, thereby synergistically stimulating the IscU-binding capacity of HscA ¹³⁰. As demonstrated by Chandramouli and Johnson, the Isc/HscA/HscB co-chaperone system facilitates efficient [2Fe-2S] cluster transfer from the IscU scaffold protein to acceptor proteins in an ATP-dependent manner ¹³¹.

Twenty-two DnaJ homologs with well-conserved J-domains can be found in the yeast S. cerevisiae (Table 2) ¹⁰. Five DnaJ homologs have been classified as type 1 (Ydj1, XDj1, Apj1, Mdj1, Scj1), four as type 2 (Caj1, Djp1, Hlj1, Sis1), and the remaining 13 as type 3 DNAJs/HSP40s ^{10, 68}. All yeast type 1 family members are true functional homologs of the E. coli DnaJ ¹⁰. Amongst them, Xdj1 and Ydj1 are closely related fulfilling analogous functions in the cytosol. Ydj1 is a molecular chaperone crucially involved in import of proteins into mitochondria, secretion of mating pheromones, and regulation of cytoplasmic HSP70s ^{10, 132}. Ydj1 which acts as a homodimer ⁶⁷ has been found to stimulate the ATPase activity of the cytosolic HSP70s in yeast, Ssa1 and Ssa2 and the re-folding of denatured polypeptides ^{133, 134}. In contrast to the type 2 DNAJ/HSP40 Sis1, Ydj1 itself can act as a chaperone in vitro, blocking protein aggregation by forming stable complexes with folding intermediates ^{133, 135}. More recent investigations suggested that Ydj1 is able to act autonomously in inhibiting prion-like aggregation of the yeast protein Ure2 by direct interacting with the native state of Ure2, prior to the onset of oligomerization ¹³⁶. These findings highlight the potential of native state stabilization as a therapeutic strategy in controlling the process of protein misfolding and aggregation.

Apj1 is a further cytosolic DNAJ/HSP40 molecule whose exact function is still unclear. Apart from its proposed chaperoning function, Apj1 has been shown as being required for growth of a natural Saccharomyces sensu stricto hybrid yeast in xylose thereby underlining its role in xylose metabolism ¹³⁷. Like Ydj1 overexpression, upregulation of Apj1 has been found to abolish growth retardation of cells expressing the yeast prion [PSI] ¹³⁸. This was a first observation of a phenotypic effect for Apj1 supporting a putative chaperone function of this type 1 DNAJ/HSP40 protein in conjunction with Ssa1/2.

Mdj1 is located to mitochondria and supports folding of proteins imported into the mitochondrial matrix by enhancing the ATPase activity of the HSP70/HSPA family member Ssc1 ¹³⁹. Scj1 represents the ER-resident member of the type 1 DNAJ/HSP40 family supporting protein folding in the lumen of the ER mediated by the yeast HSP70/HSPA family member Grp78 (BiP, Kar2) ¹⁴⁰. It is of note that the conserved Cys residues in the ZF domain of Scj1 are obviously arranged by disulphide bridges rather than the co-ordination of metal ions in the oxidizing ER environment ¹⁰.

Due to the presence of the G/F-rich repeats, four DNAJs/HSP40s in S. cerevisiae have been classified as type 2 DNAJ/HSP40, namely Caj1, Djp1, Hlj1, and Sis1. Two of them (Sis1, Djp1) are found in the cytosol, while Hlj1 represents the ER-specific and Caj1 the nuclear isoform. Sis1 has been identified as being an essential type 2 DNAJ/HSP40 family member in S. cerevisiae which forms a homodimer through a short C-terminal amino acid stretch ¹¹⁴. As demonstrated in the same study, Sis1 monomers are elongated and consist of two domains with similar folds. The Sis1 dimer has a U-shaped architecture with a large cleft formed between the two elongated monomers. Deletion of the C-terminal dimerization motif leads to severe chaperoning defects underlining the critical role of dimer formation in Sis1 chaperone function ¹¹⁴. By comparing the structures of dimeric Sis1 with that of dimeric type 1 DNAJ/HSP40 Ydj1 it became apparent that both DNAJs/HSP40s bear a large cleft between the two monomers critical for the interaction with Hsp70 ⁶⁴. However, the C-terminal dimerization motif in Sis1 is much shorter than that of Ydj1 suggesting less extensive interactions between single Sis1 monomers compared to Ydj1 ⁶⁷. Although Sis1 lacks the ZF domain, its CTD binds polypeptides to the same degree as the joined ZF/CTD of Ydj1 ¹⁴¹. Fan and collaborators present experimental evidence that conserved protein modules located within the middle of Ydj1 and Sis1 control specific functions of type I and type II DNAJs/HSP40s. As demonstrated in this study, exchangable chaperone modules of Ydj1 and Sis1 were found to control the protein folding activity, substrate binding specificity and in vivo function of these different DNAJs/HSP40s ¹⁴¹. In addition, Ydj1 and Sis1 were both able to bind phage displayed peptides enriched in aromatic and hydrophobic amino acids, but with differential selectivity. Based on these findings it can be speculated that discrepancies in the capability of type I and type II DNAJs/HSP40s to identify certain structural features in non-native polypeptides might contribute to their ability to determine certain Hsp70 functions.

Type 3 DNAJ/HSP40 family members comprise the largest subgroup of DNAJs/HSP40s in yeast. Amongst them, Swa2 is an auxilin-like protein associated with clathrin-coated vesicles in the cytosol involved in vesicular transport. Swa2 functions as a clathrin-binding protein interacting with Ssa1/2 through its J-domain thereby stimulating the uncoating of clathrin-coated vesicles ⁸⁷. Additionally, Swa2 has been identified to localize to ER membranes where it plays a pivotal role in cortical ER inheritance ¹⁴². Sec63 is an integral membrane protein spanning the ER membrane three times and showing 43% identity with DnaJ over a span of 70 amino acids ^{143, 144}. The lumenal part of Sec63 has been demonstrated to interact with the HSP70/HSPA family member HspA5 (Grp78, BiP, Kar2) through its J-domain at the translocation apparatus or translocon at the lumenal face of the ER thus playing an essential role in protein translocation into the ER ^{144, 145}.

Pam18/Tim14 is an integral protein of the mitochondrial inner membrane with a typical J-domain exposed to the matrix space ¹⁴⁶. Pam18/Tim14 is a constituent of the mitochondrial import machinery of the mitochondrial protein translocase. It stimulates the ATPase activity of the major Hsp70 of the mitochondrial matrix in yeast, Ssc1 thereby facilitation protein import into mitochondria ¹⁴⁷. This finding is supported by the observation that in vivo depletion of Pam18/Tim14 blocked protein translocation to mitochondria ¹⁴⁷.

Zuo1 (Zuotin) is a ribosome-associated Type 3 DNAJ/HSP40 which is crucially involved in ribosome biogenesis. Together with Ssz1 and Ssb1/2, it functions as a chaperone for ribosome-bound nascent polypeptide chains ¹⁴⁸. Zuotin and Ssz1 form a heterodimeric ribosome-associated complex (RAC) that is bound to the ribosome via zuotin. In vitro, RAC stimulates the translocation of a ribosome-bound mitochondrial precursor protein into mitochondria, providing evidence for its chaperone function on nascent polypeptide chains ¹⁴⁹.

Cwc23 has been described to locate to the cytosol as well as the nucleoplasm ¹⁵⁰. It plays a major role in pre-mRNA splicing and the assembly and disassembly of the spliceosome ¹⁵¹. Cwc23 may also be involved in ER-associated protein degradation (ERAD) ¹⁵² and may be required for growth at low and high temperatures ¹⁵³. Jem1 is anchored in the ER membrane with its J-domain facing the ER lumen ¹⁵⁴. It facilitates the nuclear membrane fusion during mating ^{154, 155} and plays a role in nuclear fusion through regulating the functions of the essential nuclear envelope protein Nep98p enriched in the spindle-pole body ¹⁵⁶, the sole microtubule-organizing center of budding yeast and a functional homolog of the centrosome in mammalian cells ¹⁵⁷.

The functions of the remaining type 3 DNAJs/HSP40s from yeast are unclear up to date. The group of Lars M. Steinmetz experimentally validated the localization of Jid1 in mitochondria ¹⁵⁸, while Erj5 has been identified to associate with the ER ^{150, 159}. Jjj1-3 can be found in the cytosol and nucleus ¹⁵⁰. Jjj3 has recently been shown to exhibit an iron-binding property comparable to that of its human ortholog, DnaJC24/Dph4, highlighting the conservation of iron sequestration across species ¹⁶⁰.

The genome of S. cerevisiae also encodes three J-like proteins, termed Jlp1/2 and Pam16/Tim16 (for a review see Walsh et al., 2004 ¹⁰). Only little information is available on these molecules. For instance, Jlp1 bears a Tyr residue in place of the His in the consensus HPD motif and its subcellular location is still unclear. Meanwhile it became apparent that Jlp1 acts as an alpha-ketoglutarate-dependent dioxygenase active on sulfonates thus mediating organosulfur degradation ¹⁶¹. Jlp2 is a cytosolic DNAJ/HSP40 with unknown function whose J-domain shares high significance with the J-domain of the ER-resident Sec63, but harbors an Ala residue in place of the Pro residue in the HPD motif ^{10, 150}. In contrast, Pam16/Tim16 is a peripheral membrane protein of the mitochondrial inner membrane and part of the mitochondrial Tim23 preprotein translocase ^{162, 163}. According to Frazier et al., Pam16/Tim16 interacts with Pam18/Tim14 and is required for the association of Pam18/Tim14 with the presequence translocase and for formation of an Ssc1/Tim44 complex ¹⁶³. The J-like domain in Pam16 possesses a similar length and predicted secondary structure as the corresponding Pam18/Tim14 domain, but the characteristic sequence motif HPD that is strictly conserved in all known DNAJs/HSP40s is missing in Pam16/Tim16 ¹⁶⁴. Instead, Pam16/Tim16 bears the DKE tripeptide which does not confer ability to stimulate the ATPase activity of the mtHsp70, Ssc1 ¹⁶⁴. Evidence has accumulated demonstrating that Pam16/Tim16 associates with Mdj2 and is recruited to the Tim23 translocase where it stimulates the ATPase activity of Ssc1 to the same extend as Pam18/Tim14 ¹⁶⁵.

 

Table 2: HSP40s/DNAJs of various pro- and eukaryotic organisms

Gene	Protein	Aliases	UniProt ID	Gene ID
M. mazei
Type 1 (subfamily A)
dnaJ	DnaJ	Chaperone protein DnaJ, Hsp40, NP_634528.1	P0CW07	1480846
M. acetivorans
Type 1 (subfamily A)
dnaJ	DnaJ	Chaperone protein DnaJ, Hsp40, NP_616413.1	Q8TQR1	1473367
E. coli
Type 1 (subfamily A)
dnaJ	DnaJ	Hsp40, HspJ, HSP40, GroP	P08622	944753
Type 2 (subfamily B)
cbpA	CbpA	Curved DNA-binding protein, YP_489273.1	P36659	12932265
Type 3 (subfamily C)
djlA	DjlA	DnaJ-like protein	P31680	12932622
djlB	DjlB	J domain-containing protein DjlB, YP_488937.1	P77381	12930913
djlC	DjlC	J domain-containing protein DjlC, Hsc56 co-chaperone of HscC, YP_488940.1	P77359	12932384
hscB	HscB	Hsc20, DnaJ-like molecular chaperone-specific for IscU	P0A6L9	12934043
S. cerevisiae
Type 1 (subfamily A)
YDJ1	Ydj1	Mas5, Mab3, type I Hsp40 co-chaperone YDJ1	P25491	855661
XDJ1	Xdj1	DnaJ homolog protein XDJ1, NP_013191.1	P39102	850779
APJ1	Apj1	J domain-containing protein APJ1, Ynl077w, NP_014322.1	P53940	855647
MDJ1	Mdj1	DnaJ homolog 1, mitochondrial; NP_116638.1	P35191	850530
SCJ1	Scj1	DnaJ-related protein SCJ1, NP_013941.2	P25303	855254
Type 2 (subfamily B)
SIS1	Sis1	SIS1, Sis-1, NP_014391.1	P25294	855725
DJP1	Djp1	DnaJ-like protein 1, peroxisome assembly protein 22 (Pas22), Ics1, NP_012269.1	P40564	854820
CAJ1	Caj1	CAJ1, NP_010967.3	P39101	856772
HLJ1	Hlj1	NP_013884.1, HLJ1	P48353	855196
Type 3 (subfamily C)
CWC23	Cwc23	Pre-mRNA-splicing factor CWC23, NP_011387.2, complexed with CEF1 protein 23	P52868	852749
ERJ5	Erj5	ER-localized J domain-containing protein 5, NP_116699.3	P43613	850602
SWA2	Swa2	Auxilin-like clathrin uncoating factor SWA2, bud site selection protein 24, synthetic lethal with ARF1 protein 2, NP_010606.1	Q06677	851918
SEC63	Sec63	Protein translocation protein SEC63, Sec62/63 complex 73 kDa subunit, Ptl1, Npl1, NP_014897.1	P14906	854428
PAM18	Pam18	Mitochondrial import inner membrane translocase subunit Tim14, NP_013108.1	Q07914	850694
MDJ2	Mdj2	Mitochondrial DnaJ homolog 2, NP_014071.1	P42834	855388
JAC1	Jac1	J-type co-chaperone JAC1, mitochondrial; J-type accessory chaperone 1, NP_011497.1	P53193	852866
JEM1	Jem1	DnaJ-like protein of the ER membrane 1, Kar-8, NP_012462.3	P40358	853372
JID1	Jid1	J domain-containing protein 1, NP_015386.1	Q12350	856174
JJJ1	Jjj1	J protein JJJ1, NP_014172.1	P53863	855495
JJJ2	Jjj2	J proptein JJJ2, NP_012373.2	P46997	853277
JJJ3	Jjj3	Diphthamide biosynthesis protein 4, Dph4, NP_012631.3	P47138	853560
ZUO1	Zuo1	Zuotin, DnaJ-related protein ZUO1, heat shock protein 40 homolog ZUO1, ribosome-associated complex subunit ZUO1, NP_011801.1	P32527	853202
J-like
JLP1	Jlp1	DnaJ-like protein, Jlp1p, NP_013043.1, alpha-ketoglutarate-dependent sulfonate dioxygenase	A7A0K3Q12358	850669
JLP2	Jlp2	DnaJ-like protein 2, Jlp2p, NP_013851.1	P40206	855162
PAM16	Pam16	Mitochondrial import inner membrane translocase subunit Tim16, presequence translocated-associated motor subunit PAM16, Pam16p, NP_012431.1	P42949	853340
Human
Type 1 (subfamily A)
DNAJA1	DnaJA1	HSDJ, DJ2, human DnaJ protein 2 (hDj-2), Hsj2, HSPF4, Hdj2, DjA1	P31689	3301
DNAJA2	DnaJA2	Dnj3, Dn3, HIRA-interacting protein 4, renal carcinoma antigen NY-REN-14, HIRIP4, DjA2	O60884	10294
DNAJA3	DnaJA3	Tid-1, hTID-1, hepatocellular carcinoma-associated antigen 57 (HCA57),	Q96EY1	9093
DNAJA4	DnaJA4	Dj4, Hsj-4, MST104, MSTP104, PRO1472	Q8WW22	55466
Type 2 (subfamily B)
DNAJB1	DnaJB1	Hsp40, Hdj1, hDj-1, HSPF1, Sis1, RSPH16B	P25685	3337
DNAJB2	DnaJB2	HSJ1, HSPF3, Hsj1, Dnajb10, mDj8, DSMA5	P25686	3300
DNAJB3	DnaJB3	Hcg-3, Hsj-3, Msj1, MSJ-1	Q8WWF6	414061
DNAJB4	DnaJB4	human liver DnaJ-like protein, HLJ-1, Hlj1, DjB4, Dnajw	Q9UDY4	11080
DNAJB5	DnaJB5	Hsc40, Hsp40-2, Hsp40-3	O75953	25822
DNAJB6	DnaJB6	DJ4, DnaJ, HHDJ1, HSJ-2, Hsj2, LGMD1D, LGMD1E, Mrj, MSJ-1	O75190	10049
DNAJB7	DnaJB7	Dj5, HSC3, mDj5	Q7Z6W7	150353
DNAJB8	DnaJB8	DJ6, mDj6	Q8NHS0	165721
DNAJB9	DnaJB9	ER-resident protein ERdj4; Mdg1, mDj7	Q9UBS3	4189
DNAJB11	DnaJB11	ER-resident protein ERdj3, hDj9, PWP1-interacting protein 4, APOBEC1-binding protein 2 (ABBP-2), HEDJ	Q9UBS4	51726
DNAJB12	DnaJB12	Dj10, mDj10	Q9NXW2	54788
DNAJB13	DnaJB13	testis spermatogenesis apoptosis-related gene 6/3 protein (Tsarg-6/-3),	P59910	374407
DNAJB14	DnaJB14	ER-resident EGNR9427, PRO34683, FLJ14281	Q8TBM8	79982
Type 3 (subfamily C)
DNAJC1	DnaJC1	ER-resident protein ERdj1, MTJ1, Htj1, Dnajl1	Q96KC8	64215
DNAJC2	DnaJC2	M-phase phosphatase protein 11 (MPHOSPH11), M-phase phosphoprotein 11 (MPP11), zuotin-related factor 1 (Zrf1)	Q99543	27000
DNAJC3	DnaJC3	ER-resident protein ERdj6, p58, Prkri, protein kinase inhibitor p58 (p58IPK)	Q13217	5611
DNAJC4	DnaJC4	F2, multiple endocrine neoplasia type 1 candidate protein number 18	Q9NNZ3	3338
DNAJC5	DnaJC5	cysteine string protein (Csp) alpha	Q9H3Z4	80331
DNAJC5B	DnaJC5B	Csp-beta	Q9UF47	85479
DNAJC5G	DnaJC5G	Csp-gamma	Q8N7S2	285126
DNAJC6	DnaJC6	Auxilin, mKIAA0473, DjC6, Park19	O75061	9829
DNAJC7	DnaJC7	Dj11, mDj11, DjC7, tetratricopeptide repeat protein 2 (TPR2, mTpr-2)	Q99615	7266
DNAJC8	DnaJC8	splicing protein spf31, Hspc315, Hspc331	O75937	22826
DNAJC9	DnaJC9	DnaJ protein SB73, HdjC9	Q8WXX5	23234
DNAJC10	DnaJC10	ER-resident protein ERdj5, macrothioredoxin (MTHr), JPD1	Q8IXB1	54431
DNAJC11	DnaJC11	dJ126A5.1, FLJ10737, RP1-126A5.3	Q9NVH1	55735
DNAJC12	DnaJC12	J-domain containing protein 1 (Jdp-1, mJDP1)	Q9UKB3	56521
DNAJC13	DnaJC13	DNA J-domain containing protein Rme-8 (RME-8), mKIAA0678, Gm1124	O75165	23317
DNAJC14	DnaJC14	Hdj3, hDj-3, LYST-interactimng protein 6 (LIP6), dopamine receptor-interacting protein of 78 kDa (DRIP78, Drip-78)	Q6Y2X3	85406
DNAJC15	DnaJC15	Dnajd1, cell growth-inhibiting gene 22 protein, methylation-controlled J protein(MCJ, Mcj)	Q9Y5T4	29103
DNAJC16	DnaJC16	mKIAA0962	Q9Y2G8	23341
DNAJC17	DnaJC17	DnaJ homolog subfamily C member 17; C87112	Q9NVM6	55192
DNAJC18	DnaJC18	DnaJ homolog subfamily C member 18, AU041129	Q9H819	202052
DNAJC19	DnaJC19	mitochondrial import inner membrane translocase subunit 14 (TIM14, TIMM14)	Q96DA6	131118
DNAJC20	DnaJC20	Jac1; Hsc20, HscB	Q8IWL3	150274
DNAJC21	DnaJC21	Dnaja5, GS3, Jjj1	Q5F1R6	134218
DNAJC22	DnaJC22	Wus, wurst homolog (Wurst), AI506245	Q8N4W6	79962
J-like
DNAJC23	DnaJC23	ER-resident protein ERdj2, Sec63L, Dnajc23	Q9UGP8	11231
DNAJC24	DnaJC24	CSL-type zinc finger-containing protein 3 (ZCSL3), JJJ3, diphthamide biosynthesis protein 4 (DPH4, Dph-4), 1700030A21Rik	Q6P3W2	120526
DNAJC25	DnaJC25	DnaJ homolog subfamily C member 25, bA16L21.2.1, 2010109C08Rik, 2010203O07Rik,	Q9H1X3	548645
DNAJC26	DnaJC26	Cyclin-G-associated kinase (GAK), auxilin-2	O14976	2580
DNAJC27	DnaJC27	RBJ, RabJs, Ras-associated protein 1 (Rap‑1), Rab and DnaJ-domain containing protein	Q9NZQ0	51277
DNAJC28	DnaJC28	C21orf55; C21orf78, Orf28, oculomedin	Q9NX36	54943
DNAJC29	DnaJC29	Sacsin (spastic ataxia of Charlevoix-Saguenay), SPAX6, protein phosphatase 1, regulatory subunit 138, KIAA0730	Q9NZJ4	26278
DNAJC30	DnaJC30	Williams-Beuren syndrome chromosomal region 18 protein (WBSCR18)	Q96LL9	84277