Hsp70 Chaperones


Via their interaction with client proteins, Hsp70 molecular chaperone machines function in a variety of cellular processes, including protein folding, translocation of proteins across membranes and assembly/disassembly of protein complexes. Such machines are composed of a core Hsp70, as well as a J‐protein and a nucleotide exchange factor as co‐chaperones. These co‐factors regulate the cycle of adenosine triphosphate (ATP) hydrolysis and nucleotide exchange, which is critical for Hsp70's interaction with client proteins. Cellular compartments often contain multiple Hsp70s, J‐proteins and nucleotide exchange factors. The capabilities of Hsp70s to carry out diverse cellular functions can result from either specialisation of an Hsp70 or by interaction of a multifunctional Hsp70 with a suite of J‐protein co‐chaperones. The well‐studied Hsp70 systems of mitochondria provide an example of such modes of diversification and specialisation of Hsp70 machinery, which are applicable to other cellular compartments.

Key Concepts:

  • Fundamental biochemical properties of different Hsp70 systems are very similar, yet very adaptable.

  • Diversification of Hsp70 function is often due to multiple J‐protein partners.

  • Although most Hsp70s bind a broad array of peptide sequences, some have become specialised and have a very restricted binding specificity.

Keywords: molecular chaperone; Hsp70; J‐protein; Hsp40; mitochondria; mitochondrial DNA; protein folding; protein import; iron–sulphur biogenesis; protein evolution

Figure 1.

Evolving specificity Hsp70: J‐protein machineries. Often a single Hsp70 functions with multiple J‐protein partners (centre panel). Additional specificity may evolve either by duplication of an Hsp70 gene to generate a specialised Hsp70 (right panel) or duplication of a J‐protein gene to generate an additional J‐protein partner for an existing Hsp70.

Figure 2.

Structure of J‐domain and Hsp70. The J‐domain is the defining feature of J‐proteins. Each functional J‐domain has an invariant HPD tripeptide, critical for ATPase stimulatory activity (picture based on PBD id:1XBL). The structure of Hsp70s is conserved: adenine nucleotide binds between the lobes of the ATPase domain. The peptide‐binding cleft is covered by an α helical lid. The linker allows interdomain communication (picture based on PBD id :2KHO).

Figure 3.

The Hsp70 cycle of interaction with a client protein. The universal function of the conserved J‐domain (J) of J‐proteins is stimulation of Hsp70's ATPase activity. In addition, many, but not all, J‐proteins can also bind directly to client proteins. In this way, they ‘target’ the client to Hsp70. The stimulation of Hsp70's ATPase activity is critical, because it allows Hsp70 to capture the client protein. This stimulation is important because, although the on‐rate of the client when Hsp70 is bound to ATP is rapid, the off‐rate is also rapid. However, in the ADP‐state the off rate is slow. Exchange of bound ADP for ATP completes the cycle, as Hsp70 dissociates rapidly from the client when ATP is bound. Nucleotide exchange factors (not shown) facilitate this exchange.

Figure 4.

Hsp70s and J‐proteins of the mitochondrial matrix. The generalist Hsp70 of the mitochondrial matrix (called Ssc1 in yeast) functions in general protein folding with the J‐protein Mdj1. Ssc1 also functions in protein translocation with a transmembrane J‐protein partner, Pam18. In both cases, Ssc1 interacts with numerous different client proteins. In addition, the specialised Hsp70 Ssq1 functions with the specialised J‐protein Jac1 in Fe‐S cluster biogenesis. Jac1 and Ssq1 are thought to have a single client, Isu, the scaffold on which the clusters are built. The chaperones are involved in the transfer of the cluster from Isu to a recipient protein.



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Further Reading

Conant GC and Wolfe KH (2008) Turning a hobby into a job: how duplicated genes find new functions. Nature Reviews. Genetics 9(12): 938–950.

Hartl FU and Hayer‐Hartl M (2009) Converging concepts of protein folding in vitro and in vivo. Nature Structural & Molecular Biology 16(6): 574–581.

Kampinga HH and Craig EA (2010) The Hsp70 chaperone machinery: J proteins as drivers of functional specificity. Nature Reviews. Molecular Cell Biology 11(8): 579–592.

Kampinga HH, Hageman J, Vos MJ et al. (2009) Guidelines for the nomenclature of the human heat shock proteins. Cell Stress and Chaperones 14(1): 105–111.

Mayer MP (2010) Gymnastics of molecular chaperones. Molecular Cell 39(3): 321–331.

Szklarczyk R and Huynen MA (2009) Expansion of the human mitochondrial proteome by intra‐ and inter‐compartmental protein duplication. Genome Biology 10(11): R135.

Tyedmers J, Mogk A and Bukau B (2010) Cellular strategies for controlling protein aggregation. Nature Reviews. Molecular Cell Biology 11(11): 777–788.

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Craig, Elizabeth A, and Marszalek, Jaroslaw(Mar 2011) Hsp70 Chaperones. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0023188]