Not all J domains are created equal: Implications for the specificity of Hsp40–Hsp70 interactions

Abstract

Heat shock protein 40s (Hsp40s) and heat shock protein 70s (Hsp70s) form chaperone partnerships that are key components of cellular chaperone networks involved in facilitating the correct folding of a broad range of client proteins. While the Hsp40 family of proteins is highly diverse with multiple forms occurring in any particular cell or compartment, all its members are characterized by a J domain that directs their interaction with a partner Hsp70. Specific Hsp40-Hsp70 chaperone partnerships have been identified that are dedicated to the correct folding of distinct subsets of client proteins. The elucidation of the mechanism by which these specific Hsp40-Hsp70 partnerships are formed will greatly enhance our understanding of the way in which chaperone pathways are integrated into finely regulated protein folding networks. From in silico analyses, domain swapping and rational protein engineering experiments, evidence has accumulated that indicates that J domains contain key specificity determinants. This review will critically discuss the current understanding of the structural features of J domains that determine the specificity of interaction between Hsp40 proteins and their partner Hsp70s. We also propose a model in which the J domain is able to integrate specificity and chaperone activity.Keywords: J domain; DnaJ; Hsp70; specificity determinants Hsp40 and Hsp40-like proteinsThe heat shock protein 70 family (Hsp70) of molecular chaperones is a major component of the cellular chaperone network and the stress response. Hsp70 proteins are regulated by several co-chaperones, in particular the heat shock protein 40 (Hsp40) family, which stimulates Hsp70 ATP hydrolysis, thereby regulating Hsp70 client protein interactions. The Hsp40 family of proteins, including so-called Hsp40-like proteins, are defined by the presence of the J domain, a 70-amino-acid domain with similarity to the initial 73 amino acids of the Escherichia coli Hsp40 called DnaJ (Pellecchia et al. 1996). In addition to the J domain, Hsp40 and Hsp40-like proteins may have certain other structural features that are conserved from E. coli DnaJ (Ohki et al. 1986;Cheetham and Caplan 1998). E. coli DnaJ is comprised of four canonical domains, a J domain, a Gly/Phe-rich region, four cysteine repeats, and an uncharacterized C terminal region. A schematic of the domains present in E. coli DnaJ is given in Figure 1.

Reconstitution of a Mycobacterium tuberculosis proteostasis network highlights essential cofactor interactions with chaperone DnaK

“…Analysis of J proteins from species as diverse as bacteria and humans has shown that a highly conserved "HPD" motif in the N terminus is involved in proper function (26,43). A histidine-toglutamine mutation in the motif was originally identified as a heat-sensitive mutant in E. coli and has been studied in other homologs (44)(45)(46).…”

“…The reaction cycle of DnaK is regulated by cofactors called J proteins (DnaJ in bacteria, Hsp40 in eukaryotes) and the nucleotide exchange factor (NEF) GrpE (25,26). Bacteria have only one NEF, and GrpE is essential in Msm (13).…”

OWL1: An Arabidopsis J-Domain Protein Involved in Perception of Very Low Light Fluences

“…The type III J-domain proteins, to which OWL1 belongs, represent a functionally distinct group from the DNAJ proteins and are very heterogenous. They have been suggested not to act as chaperones and seem not to bind to non-native polypeptides, although they are still able to recruit Hsp70 proteins, as the binding motifs are highly conserved (Walsh et al, 2004;Hennessy et al, 2005).…”

Dissection of a viral autoprotease elucidates a function of a cellular chaperone in proteolysis

“…Moreover, Jiv90 does not comprise the J domain, an essential determinant for the interaction of J-domain proteins with chaperones of the Hsp70 family (19). Accordingly, the Jiv-mediated activation of the NS2 protease for cis and trans cleavage is most likely occurring independent of chaperones of the Hsp70 family.…”