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1 Department of Biochemistry, Microbiology and Biotechnology, Rhodes University, Grahamstown 6140, South Africa
2 Department of Medical Biochemistry and Molecular Biology, Universität des Saarlandes, Homburg D66421, Germany
3 Division of Pathology, Institute of Ophthalmology, University College London, London EC1V 9EL, UK
Reprint requests to: Gregory L. Blatch, Department of Biochemistry, Microbiology and Biotechnology, Rhodes University, Grahamstown 6140, South Africa; e-mail: g.blatch{at}ru.ac.za; fax: +27-46-622-3984.
(RECEIVED March 15, 2005; FINAL REVISION April 18, 2005; ACCEPTED April 27, 2005)
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Abstract |
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 TOP Abstract Hsp40 and Hsp40-like proteinsSubdivision and nomenclature of...Hsp40s integrate the ATPase...Binding sites and binding...Specificity of Hsp40-Hsp70...Substitutions in the J...References |
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Keywords: J domain; DnaJ; Hsp70; specificity determinants
Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.051406805.
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Hsp40 and Hsp40-like proteins |
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TOPAbstractHsp40 and Hsp40-like proteinsSubdivision and nomenclature of...Hsp40s integrate the ATPase...Binding sites and binding...Specificity of Hsp40-Hsp70...Substitutions in the J...References |
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. The structures contain four 
-helices (helices I–IV), with a loop region containing a highly conserved tripeptide of histidine, proline, and aspartic acid (HPD motif) located between helices II and III (Qian et al. 1996). The HPD motif is present in all known J domains, with the exception of the ring infected erythrocyte surface antigen (RESA) proteins of Plasmodium falciparum (Bork et al. 1992), the E. coli DjlB/DjlC family of proteins (Kluck et al. 2002), and the yeast protein Tim16/Pam16 (Walsh et al. 2004). Binding inhibition studies using peptides suggested that the minimal Hsp70-binding site in the J domain of the yeast Hsp40, Ydj1, was between amino acids 2 and 35, which included helices I and II, and the HPD motif (Tsai and Douglas 1996; Greene et al. 1998). The auxilin J domain, like that of Sec63 and Scj1, contains an extra loop region between helices I and II, which is proposed to act as an extended interface for interaction with Hsc70 during clathrin uncoating (Jiang et al. 2003). The J domain also appears to be flexible in structure, and an induced-fit mechanism has been proposed, with the HPD motif aiding in the alteration of the orientation of the charged residues in helix II, such that helix II can interact correctly with the ATPase domain of a partner Hsp70 (Huang et al. 1999; Berjanskii et al. 2002; Landry 2003).
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Subdivision and nomenclature of Hsp40 and Hsp40-like proteins |
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TOPAbstractHsp40 and Hsp40-like proteinsSubdivision and nomenclature of...Hsp40s integrate the ATPase...Binding sites and binding...Specificity of Hsp40-Hsp70...Substitutions in the J...References |
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Hsp40s integrate the ATPase and chaperone activities of Hsp70s |
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TOPAbstractHsp40 and Hsp40-like proteinsSubdivision and nomenclature of...Hsp40s integrate the ATPase...Binding sites and binding...Specificity of Hsp40-Hsp70...Substitutions in the J...References |
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In E. coli, the protein folding cycle has been proposed to start when DnaJ presents a client protein to DnaK (Szabo et al. 1994; McCarty et al. 1995; Russell et al. 1999) or binds to an already existing DnaK–client protein complex (Pierpaoli et al. 1997, 1998; Gisler et al. 1998; Nagata et al. 1998). It is likely that the nature of the amino acid sequence of the client protein dictates which mechanism is employed for entry of the client protein and DnaJ into the cycle (Pierpaoli et al. 1998), and that, in general, different partner Hsp40 or Hsp40- like proteins may deliver different client proteins to an Hsp70 (Misselwitz et al. 1998). The interaction of E. coli DnaJ with DnaK allows DnaK to attain a high client protein-affinity conformational state after the hydrolysis of ATP (Szabo et al. 1994), and in the process generates a DnaK–client–DnaJ ternary complex (Han and Christen 2003). Thus, upon hydrolysis of ATP a conformational shift occurs in DnaK, locking the client protein into its peptide binding cleft (Moro et al. 2003). DnaJ leaves the DnaK–client protein complex, and GrpE then stimulates the dissociation of ADP from the DnaK ATPase domain, allowing replacement with ATP. This triggers the release of the client protein, which may now fold correctly via a folding intermediate form, or rebind to DnaK and restart the cycle, or associate with other chaperone systems such as the chaperonin GroEL/ES system.
The Hsp70 ATPase and protein folding cycle in eukaryotes
A similar ATPase cycle occurs for eukaryotic Hsp70s, in the presence of Hsp40 or Hsp40-like proteins and nucleotide exchange factors. GrpE homologs do not appear to be present in the cytosol of eukaryotes (Schumacher et al. 1996), although they have been shown to be present in mitochondria (Bolliger et al. 1994). However, other nucleotide exchange factors (Bag1 and HspBP1) have been identified in the eukaryotic cytosol that appear to have different effects on the function of Hsp70s (Kabani et al. 2003; Shomura et al. 2005). In the eukaryotic cytosol, the Hsp70 ATPase and client protein folding cycles are embedded within a complex network of protein folding pathways regulated by specialized co-chaperones. An Hsp40 or Hsp40-like protein stimulates the ATPase activity of Hsp70, causing the formation of a client protein-bound Hsp70 as described for the E. coli system. The Hsp70–client protein conformation can then be further stabilized by the Hsc70-interacting protein (Hip). Hip is involved in the stabilization of the ADP-bound form of Hsp70 in eukaryotic systems (Höhfeld et al. 1995). This allows further time for the unfolded polypeptide to attain a native or native-like conformation. The client protein may be released from Hsp70 to fold correctly on its own or it may be passed onto other chaperone systems (e.g., the chaperonin system or the Hsp90 chaperone machinery) (Schumacher et al. 1996).
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Binding sites and binding determinants within the Hsp70–J domain pairing |
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TOPAbstractHsp40 and Hsp40-like proteinsSubdivision and nomenclature of...Hsp40s integrate the ATPase...Binding sites and binding...Specificity of Hsp40-Hsp70...Substitutions in the J...References |
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In vitro analysis of the C-terminal region of rat Hsc70, including the -helical lid region, indicated that this region also possessed a binding site for Hsp40 (Freeman et al. 1995; Demand et al. 1998). However, for DnaK two observations suggest that the region N-terminal to this proposed C-terminal binding site, including but not limited to the ATPase domain, probably contains the major site of interaction with DnaJ. First, a truncated E. coli DnaK mutant lacking the last 100 residues at the C terminus was still capable of having its ATPase activity stimulated by E. coli DnaJ and of binding to E. coli DnaJ, albeit at a slightly reduced level compared to the binding of full-length DnaK (Gässler et al. 1998; Suh et al. 1999). Second, under conditions where full-length DnaK functionally interacted with DnaJ, the ATPase core of DnaK in isolation (residues 1–385) was not able to bind to DnaJ, nor have its ATPase activity stimulated by DnaJ (Gässler et al. 1998). Blocking of the peptide binding domain of DnaK also abrogated ATPase stimulation by DnaJ. Thus, when Val436 in the peptide binding region was mutated to phenylalanine, a mutation that inhibited the binding of client protein to the peptide binding domain, DnaJ was unable to stimulate the ATPase activity as efficiently (Laufen et al. 1999). These data imply that binding of a client protein and/or DnaJ to the peptide binding site of DnaK is important for ATPase stimulation.
Binding sites on Hsp40-like proteins
The amino acids on Hsp40 and Hsp40-like proteins that are involved in the binding to a partner Hsp70 are less precisely defined. While there is evidence to suggest that the Gly/Phe region may be important for substrate specificity and binding to Hsp70 (Yan and Craig 1999; Fan et al. 2004), it is now well established that Hsp40 and Hsp40-like proteins interact with Hsp70s primarily through the J domain and in particular the HPD motif. Substitutions of the HPD residues abolish the stimulation of the Hsp70 ATPase activity (Tsai and Douglas 1996). However, other residues and regions outside the HPD motif, especially helix II, are gradually being implicated in the interaction of Hsp40 and Hsp40- like proteins with Hsp70 (Lu and Cyr 1998; Genevaux et al. 2002, 2003; Hennessy et al. 2005). For example, the ability of peptides corresponding to various portions of the Ydj1 J domain to compete with full-length Ydj1 for interaction with Hsp70 (Lu and Cyr 1998) showed that helix II and the HPD motif were almost as effective as the full-length J domain in perturbing Hsp70–Ydj1 interactions. However, helix III and the HPD motif were also shown to be almost as capable of affecting the interaction, but a competing peptide of helix I was not (Lu and Cyr 1998). Neither helix II nor helix III was as effective as the full-length J domain. Therefore, while the minimal region for the interaction of Ydj1 with Hsp70 was found to be located in helix II and the loop region of the J domain, other parts of the J domain were also required for complete binding.
A QKRAA motif has been identified in helix IV of the J domain in E. coli DnaJ, and QKRAA-containing peptides have been shown to be recognized by DnaK and to prevent DnaJ binding to DnaK (Auger and Roudier 1997). The lysine and arginine residues present in that motif are conserved in most J domains (Hennessy et al. 2000), and mutations of these residues in the J domain of E. coli DnaJ caused partial abrogation of the interaction of the J domain with DnaK (Suh et al. 1999). Furthermore, Suh et al. (1999) proposed that the QKRAA motif might be a binding site for the interaction of DnaJ with DnaK by transiently interacting with the peptide binding domain.
There is strong evidence that the binding of E. coli DnaJ to DnaK is bipartite in nature, with two distinct DnaJ binding sites on DnaK with differing affinities (Karzai and McMacken 1996; Mayer et al. 1999; Suh et al. 1999). In addition, the nature of this bipartite interaction is central to the mechanism by which DnaJ targets client proteins to DnaK for effective assisted protein folding. While the presence of client protein and an Hsp40 or Hsp40-like protein are required for maximal stimulation of Hsp70 ATP hydrolysis activity, the mechanism of assisted protein folding relies on the J domain binding to Hsp70 in such a manner that ensures that ATP hydrolysis is tightly coupled to client protein binding (Jordan and McMacken 1995; Laufen et al. 1999; Wittung-Stafshede et al. 2003).
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Specificity of Hsp40–Hsp70 interaction |
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TOPAbstractHsp40 and Hsp40-like proteinsSubdivision and nomenclature of...Hsp40s integrate the ATPase...Binding sites and binding...Specificity of Hsp40-Hsp70...Substitutions in the J...References |
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J domain swapping experiments
Substitution of a J domain from one protein by a J domain from another has been a fruitful area in terms of establishing the elements of specificity of interaction. Results from various experiments are shown in Table 1. One of the first experiments conducted showed that the J domain from the yeast mitochondrial Hsp40 protein Mdj1 (Type I) could effectively substitute for the J domain of E. coli DnaJ (Deloche et al. 1997). Equally, the J domain from the Type III E. coli Hsp40-like protein DjlA could effectively substitute for E. coli DnaJ’s J domain (Genevaux et al. 2001). However, both DnaJ and DjlA interact with the same Hsp70, namely DnaK. The J domain from another Type III E. coli Hsp40-like protein, DjlC (which interacts with heat shock cognate protein C/62 kDa [HscC/Hsc62]) was not able to replace the J domain of E. coli DnaJ in in vivo complementation assays, implying that it was unable to interact with DnaK (Kluck et al. 2002).
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Domain swapping experiments have also been performed using the J domains from the viral large T antigen proteins. J domains from these proteins used to substitute for the J domains from E. coli DnaJ and yeast Ydj1 gave fully functional chimeric DnaJ and Ydj1 proteins (Kelley and Georgopoulos 1997). The converse, however, did not apply. Substitutions of either the DnaJ or the Ydj1 J domains in the large T antigen only gave partially functional chimeras, with the inability to perform some of their cellular roles (Sullivan et al. 2000b). SV40 T antigen chimeras containing the J domains from Hdj1 or Hsj1 were able to function in the reduction of p130 and phosphorylation of p130 (Stubdal et al. 1997) which was important for T antigen mediated cellular transformation. Large T antigen proteins containing the J domains from Hsj1 or DnaJ2 (also known as Hsj2/Hdj2) could promote viral replication (Campbell et al. 1997). Recently a mammalian J domain was shown to be able to substitute for the J domains from E. coli DnaJ and yeast Ydj1 (Yan et al. 2002). The J domain from P58IPK, a mammalian protein that also contains tetratricopeptide repeat motifs, could functionally replace the DnaJ and Ydj1 J domains in vivo using complementation assays. Mutations in the HPD motif of the chimeric proteins prevented successful complementation for the lack of DnaJ in E. coli or Ydj1 in yeast knockout strains (Yan et al. 2002). This is the only published example of a J domain from a mammalian Type III Hsp40-like protein that is able to functionally replace the J domain in a yeast and a prokaryotic Type I Hsp40 protein. However, the meaning of these findings for J domain specificity is debatable, since the J domain of P58IPK does not appear to be critical for any of the functions of P58IPK. To date no systematic analysis has been conducted on the interchangeability of J domains between all the Type I, II, and III Hsp40 and Hsp40-like proteins from any one cell type, compartment, or system.
Specificity of the Hsp40–Hsp70 Interaction in E. coli
As E. coli has no compartments within the cytoplasm, proteins containing J domains can potentially interact with all Hsp70s in the cell. This could allow for a situation whereby the levels of nonspecific Hsp40–Hsp70 interactions could interfere with productive interactions. E. coli has three identified Hsp70s, DnaK, HscA/Hsc66 (heat shock cognate protein A/66 kDa) (Lelivelt and Kawula 1995; Vickery et al. 1997; Silberg and Vickery 2000), and HscC/Hsc62 (Kluck et al. 2002; Yoshimune et al. 2002). It also has several identified Hsp40 and Hsp40-like proteins, DnaJ, CbpA (Ueguchi et al. 1994), DjlA (Clarke et al. 1996), Hsc20 (Silberg et al. 1998), DjlB, and DjlC/Hsc56 (Kluck et al. 2002; Yoshimune et al. 2002). All these Hsp40 and Hsp40-like and Hsp70 proteins have defined partnerships (Fig. 4).
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General binding and specificity determinants
Several lines of evidence suggest that the major site of interaction of an Hsp40 or Hsp40-like protein with its partner Hsp70 resides in the J domain. First, the J domain alone has been shown to be sufficient to bind and stimulate a partner Hsp70 (Wittung-Stafshede et al. 2003), and substitutions in the HPD motif of the J domain abolish functional interactions with partner Hsp70s (Mayer et al. 1999; Kluck et al. 2002). Second, there are Hsp40-like proteins that consist almost solely of a J domain (e.g., the tiny T antigen; Riley et al. 1997) or have a J domain region isolated within a cellular compartment (e.g., the Sec63 J domain, which protrudes into the ER lumen; Schlenstedt et al. 1995), implying that any ability of these Hsp40-like proteins to interact with a partner Hsp70 must reside primarily in the J domain. Third, the fact that only the J domain residues show conservation across all Hsp40 and Hsp40-like proteins suggests that the J domain is the key component in a conserved mechanism of interaction between these proteins and partner Hsp70s. However, these arguments only apply to a general binding mechanism applicable to most Hsp40–Hsp70 interactions, as opposed to a mechanism for specificity determination.
It is important to distinguish between general binding determinants that are important in the majority of Hsp40–Hsp70 partnerships, and specificity determinants, which are important in specific Hsp40–Hsp70 partnerships. The inability of all Hsp40 and Hsp40-like proteins to interact with all Hsp70s implies a level of mechanistic binding discrimination. These discriminatory binding determinants could reside in the poorly conserved regions of Hsp40 and Hsp40-like proteins that occur beyond the J domain. However, the same lines of evidence that suggest that general binding determinants reside in the J domain can also be used to argue that specificity determinants reside in the J domain. In addition, if one considers that affinity plays a role in specificity, certain of the general binding determinants could also be involved in specificity determination. J domain-based specificity determination is not exclusive, and mechanisms for cellular regulation of specific interactions could occur at the level of colocalization of partnerships to specific organelles or tissues (in eukaryotes) or at the level of coexpression under certain special conditions. In addition, one cannot exclude the possibility that there exist proteins whose functions are to keep Hsp70 and an Hsp40 or Hsp40-like partner protein in a complex, and that this clamp provides specificity (e.g., in Thermus thermophilus; Motohashi et al. 1994, 1996).
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Substitutions in the J domain and a model for specificity |
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TOPAbstractHsp40 and Hsp40-like proteinsSubdivision and nomenclature of...Hsp40s integrate the ATPase...Binding sites and binding...Specificity of Hsp40-Hsp70...Substitutions in the J...References |
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. From an analysis of conserved J domain residues (Hennessy et al. 2005), several residues can be defined as being important for J domain function and can be divided into two main categories, namely, charged residues/ motifs and hydrophobic residues (Fig. 5). Highly conserved charged residues and motifs include the positively charged residues located on helix II, negatively charged residues on helix IV, the KFK motif on helix III (Hennessy et al. 2000), and the QKRAA motif on helix IV (Auger and Roudier 1997). Highly conserved hydrophobic residues include conserved leucines on helices I and III, aromatic residues on helix I, and an alanine residue on helix III (Hennessy et al. 2000). The highly conserved charged residues/motifs are likely to be important in J domain structure and/or function, whereas the conserved hydrophobic residues are likely to be mainly critical for maintaining the structural integrity of the J domain. Some of these residues are discussed in more detail below.
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). This is similar to the "client protein" function initially envisaged for the Gly/Phe-rich region (Karzai and McMacken 1996). This proposal is partly consistent with the modeled auxilin–Hsc70 complex (Gruschus et al. 2004a), which predicted that sequences near helix I of the J domain (helix 2 of auxilin) interacted with the peptide binding domain of Hsc70. We envisage that these J domain contacts with Hsp70 are highly dynamic interactions and that the nature of binding changes in the presence of client protein. An appropriate client protein at the right concentration may enter the system by direct interaction with Hsp70 or through presentation by an Hsp40 or Hsp40-like partner protein. In either scenario, we propose that the client protein would have to have a high enough affinity for Hsp70, and be at the right concentration, before it can compete effectively with the J domain of an Hsp40 or Hsp40-like partner protein, so as to result in a protein triad that fully and appropriately couples the stimulation of ATP hydrolysis and the conformational changes necessary for client protein capture by Hsp70. Therefore the specificity of the system resides at the level of both the client protein and the J domain. We propose that an inappropriate client protein with a low capacity to be chaperoned (e.g., peptides from protein degradation) may not be able to compete with the J domain and will be excluded from the Hsp40–Hsp70 system, and only once an appropriate client protein and an Hsp40 or Hsp40-like partner protein are present simultaneously will a productive interaction occur with a particular Hsp70. This proposed model for the specificity of J domain function has implications for the mechanism of J domain action, especially when one considers the direct dynamic binding of the J domain to two different sites on an Hsp70 (ATPase and peptide binding domains). In the absence of substrate there are potentially two independent binding interactions occurring simultaneously between two different surfaces of the J domain with two different surfaces of an Hsp70, thereby creating dynamic strain/tension in the system that is delicately poised to facilitate the coupling of ATP hydrolysis with conformational change, should a suitable client protein enter the system. Once a suitable client protein enters the system, binding of the J domain to the ATPase domain could be favored, perhaps through conformational bias of an induced fit conformation, and in the process ATP hydrolysis would be coupled to the conformational changes necessary for the Hsp70 to capture the client protein in its peptide binding domain. Consequently, amino acid substitutions (e.g., D35N on the J domain or changes to the ATPase binding cleft residues of an Hsp70) that stabilize a J domain conformation or set of conformations that favor binding to one of the binding sites on an Hsp70, will disrupt the train/tension in the Hsp40–Hsp70 system required for a fully functional Hsp40–Hsp70–client protein interaction.
To fully define the specificity features of the J domain a systematic approach of rational mutagenesis and domain swapping experiments is required. For example, a comparative analysis of the ER-based Hsp40 and Hsp40-like proteins (ERj1–5) with the cytosolic Hsp40 and Hsp40-like proteins of mammalian or yeast systems would be a worthwhile and informative study. Ultimately the acquisition of the three-dimensional structures of Hsp40–Hsp70 complexes, perhaps using modified versions of Hsp40 or Hsp40-like proteins that stably associate with a partner Hsp70 (e.g., a J–D35N– DnaK ATPase domain complex), will help to resolve the molecular basis of the Hsp40–Hsp70 interaction.
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Footnotes |
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Acknowledgments |
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References |
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TOPAbstractHsp40 and Hsp40-like proteinsSubdivision and nomenclature of...Hsp40s integrate the ATPase...Binding sites and binding...Specificity of Hsp40-Hsp70...Substitutions in the J...References |
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