HSP40/DNAJ Chaperones


Members of the HSP40/DNAJ family comprise one of the largest groups of molecular chaperones, and are present in all living organisms from bacteria to humans. The hallmark of DNAJs is the presence of a J‐domain, which is crucial for interaction with HSP70. DNAJs can be seen as the workforce that steers HSP70 machines, regulating client input and specificity. The different DNAJs are involved in processes such as (re)folding, intracellular transport across membranes, protein modifications, remodelling of protein complexes and protein degradation. In particular, different DNAJs are able to suppress aggregate formation of several amyloidogenic proteins linked to human diseases. On the other hand, mutations in many DNAJs give rise to a wide range of pathologies, attesting to their fundamental role in cellular homeostasis and general protein quality control.

Key Concepts

  • Chaperome is the interconnected network of chaperones and cochaperones that works cooperatively to maintain protein homeostasis (Brehme and Voisine, 2016).
  • Molecular chaperone is a protein that assists folding, refolding, disaggregation and/or assembly of macromolecular complexes, but is not a permanent component of the final, native, functional structure. Chaperones can act as substrate ‘foldases’ in an ATP‐dependent manner or as ‘holdases’ in an ATP‐independent manner.
  • Folding is the formation of an energetically stable three‐dimensional conformation specific to a given protein sequence, also known as the native, functional conformation. On the other hand, misfolding happens when the protein does not reach its native conformation on a biologically relevant timescale.
  • Amyloidogenic proteins are proteins with a high tendency of folding into energetically favourable aggregates, which catalyse the formation of protein fibrils and plaques, and are associated to cellular toxicity and degeneration.
  • Protein disaggregation is the disentangling of protein aggregates through their resolubilization by chaperones, followed by their refolding or degradation.

Keywords: HSP40/DNAJ; molecular chaperone; heat shock protein; amyloidogenic protein; protein quality control

Figure 1. The interconnected relationship of DNAJ proteins in the context of HSP70 machines. Schematic interaction map of human DNAJs from classes A, B and C (blue circles) with molecular chaperones from the HSP70 family (green circles) and nucleotide exchange factors (NEFs, brown circles). Experimentally validated protein–protein interactions are represented by lines, colour coded according to the classes of the interacting partners (for instance, blue for DNAJ–DNAJ or green for DNAJ–HSP70 interactions). The map was generated using the STRING protein interaction tool version 10.5 (https://string‐db.org/). Actual distances between nodes are not drawn to scale, and nonchaperone interactors were omitted for clarity. DNAJB3, HSPA7 and BAG1L were not found in the STRING database. The DNAJC members 14, 15, 20, 27, 28 and the NEFs BAG6 and BAP did not show any direct DNAJ, HSP70 or NEF interaction, and were thus omitted from the figure.
Figure 2. Structure of J‐domain and DNAJ classes A, B and C (types I, II and II). (a) Representation of the secondary structure of the J‐domain of human DNAJB1 (PDB code 1HDJ). J‐domains are formed by four α‐helices with the conserved His‐Pro‐Asp (HPD) motif located in the loop between helices II and III. (b) Domain organisation of representative DNAJ proteins from classes I, II and III with typical examples for each group from Saccharomyces cerevisiae (Sc). The structure of amino acids 110–378 from scYdj1 (reconstruction of protein data bank (PDB) codes 1NLT and 1XAO) and 180–349 from scSis1 (PDB code 1C3G) are shown. Both proteins form homodimers predominantly composed of β‐sheets, and each monomer comprises two adjacent domains referred to as C‐terminal domain I (CTDI) and CTDII. The zinc fingers Zn1 and Zn2 that define the class A (type I) DNAJs like scYdj1 are located represented in orange.
Figure 3. Selected DNAJ proteins display an isoform‐specific expression pattern in different tissues. Isoform‐ and tissue‐specific messenger RNA expression data from human DNAJB2, DNAJB6 and DNAJB12 (ENSEMBL protein codes between parentheses) were obtained from the GTEx portal (https://www.gtexportal.org/home/) and are expressed as blue and green lines. RPKM, reads per kilobase per million.
Figure 4. Messenger RNA (mRNA) expression levels of human DNAJ proteins shows tissue‐specific patterns. mRNA sequencing data for all available DNAJ proteins in different tissues from more than 700 donors was obtained from the GTEx portal (https://www.gtexportal.org/home/) and analysed through the R2 Genomics Analysis and Visualization Platform (http://hgserver1.amc.nl/cgi‐bin/r2/main.cgi) using log2 normalisation. Data on the testis‐specific DNAJB3, DNAJB8, DNAJC5B and DNAJC5G.


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Further Reading

Bukau B, Weissman J and Horwich A (2006) Molecular chaperones and protein quality control. Cell 125 (3): 443–451.

Chiti F and Dobson CM (2017) Protein misfolding, amyloid formation, and human disease: a summary of progress over the last decade. Annual Review of Biochemistry 86 (1): 27–68.

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Reis SD, Pinho BR and Oliveira JMA (2016) Modulation of molecular chaperones in Huntington's disease and other polyglutamine disorders. Molecular Neurobiology 54 (8): 5829–5854.

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Musskopf, Maiara K, de Mattos, Eduardo P, Bergink, Steven, and Kampinga, Harm H(May 2018) HSP40/DNAJ Chaperones. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0027633]