Article

Mayer M, Bukau BHsp70 chaperones: Cellular functions and molecular mechanism. Cell Mol Life Sci 62: 670-684

Zentrum für Molekulare Biologie (ZMBH), Universität Heidelberg, Im Neuenheimer Feld 282, 69120, Heidelberg, Germany.
Cellular and Molecular Life Sciences CMLS (Impact Factor: 5.81). 04/2005; 62(6):670-84. DOI: 10.1007/s00018-004-4464-6
Source: PubMed

ABSTRACT

Hsp70 proteins are central components of the cellular network of molecular chaperones and folding catalysts. They assist a large variety of protein folding processes in the cell by transient association of their substrate binding domain with short hydrophobic peptide segments within their substrate proteins. The substrate binding and release cycle is driven by the switching of Hsp70 between the low-affinity ATP bound state and the high-affinity ADP bound state. Thus, ATP binding and hydrolysis are essential in vitro and in vivo for the chaperone activity of Hsp70 proteins. This ATPase cycle is controlled by co-chaperones of the family of J-domain proteins, which target Hsp70s to their substrates, and by nucleotide exchange factors, which determine the lifetime of the Hsp70-substrate complex. Additional co-chaperones fine-tune this chaperone cycle. For specific tasks the Hsp70 cycle is coupled to the action of other chaperones, such as Hsp90 and Hsp100.

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    • "Classical molecular chaperones in the ER are functionally similar to counterparts in other folding environments such as the HSP70 family member BiP (Kar2 in yeast). Similar to other HSP70s in the cytosol, mitochondria, etc., BiP transiently binds hydrophobic patches of ER client proteins and thereby protects them from undergoing inappropriate interactions with other proteins (Mayer and Bukau, 2005). BiP is an ATPase and cycles of client binding and release require ATP hydrolysis. "

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    • "Two additional spots corresponding to Ssb1 (member of Hsp70 family) involved in oxidative stress response were identified. Hsp70 is the family of universal cytosolic chaperones involved in folding of damaged but repairable proteins and in the degradation of those that are damaged beyond repair [9]. Finally, two other proteins, phosphomannomutase and ubiquitin, are involved in processing and transport of proteins (Fig. 4D). "
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    • "We chose this assay because an increase in the ATPase activity of Hsp70 in the ! 6! presence of both a J-protein co-chaperone and a client protein is a hallmark of a productive chaperone interaction (Fig. 3A) (Mayer and Bukau 2005). Two parameters can be determined in such analyses: the maximal stimulation achievable (V m ) and the concentration at which 50% V m is attained (C 0.5 ). "
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    ABSTRACT: Biogenesis of iron–sulfur clusters (FeS) is a highly conserved process involving Hsp70 and J-protein chaperones. However, Hsp70 specialization differs among species. In most eukaryotes, including Schizosaccharomyces pombe, FeS biogenesis involves interaction between the J-protein Jac1 and the multifunctional Hsp70 Ssc1. But, in Saccharomyces cerevisiae and closely related species, Jac1 interacts with the specialized Hsp70 Ssq1, which emerged through duplication of SSC1. As little is known about how gene duplicates affect the robustness of their protein interaction partners, we analyzed the functional and evolutionary consequences of Ssq1 specialization on the ubiquitous J-protein cochaperone Jac1, by comparing S. cerevisiae and S. pombe. Although deletion of JAC1 is lethal in both species, alanine substitutions within the conserved His–Pro–Asp (HPD) motif, which is critical for Jac1:Hsp70 interaction, have species-specific effects. They are lethal in S. pombe, but not in S. cerevisiae. These in vivo differences correlated with in vitro biochemical measurements. Charged residues present in the J-domain of S. cerevisiae Jac1, but absent in S. pombe Jac1, are important for tolerance of S. cerevisiae Jac1 to HPD alterations. Moreover, Jac1 orthologs from species that encode Ssq1 have a higher sequence divergence. The simplest interpretation of our results is that Ssq1’s coevolution with Jac1 resulted in expansion of their binding interface, thus increasing the efficiency of their interaction. Such an expansion could in turn compensate for negative effects of HPD substitutions. Thus, our results support the idea that the robustness of Jac1 emerged as consequence of its highly efficient and specific interaction with Ssq1.
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