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


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. "
    Encyclopedia of Cell Biology, Vol 2, Edited by Ralph A Bradshaw and Philip D Stahl (Editors-in-Chief, 01/2016: pages 156-167; Academic Press.
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    • "In its ADP ribosylated form, BiP is locked into an inactive state with low affinity for its substrates (Freiden et al., 1992). ADP ribosylation affects residues in BiP that interfere with the allosteric coupling of ATP binding and hydrolysis in BiP's nucleotide binding domain (NBD) to the affinity of its substrate binding domain (SBD) for unfolded proteins (Chambers et al., 2012), thus targeting the basic chaperoning mechanism used by all Hsp70/DnaK family members (Mayer and Bukau, 2005). A recent study reveals that the same circumstances that promote ADP ribosylation of BiP are also associated with rapidly reversible formation of an ester bond between threonine 366 in the NBD and adenosine monophosphate to yield BiP AMPylation, an inactivation modification (Ham et al., 2014). "
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    ABSTRACT: DnaK/Hsp70 chaperones form oligomers of poorly understood structure and functional significance. Site-specific proteolysis and crosslinking were used to probe the architecture of oligomers formed by the endoplasmic reticulum (ER) Hsp70, BiP. These were found to consist of adjacent protomers engaging the interdomain linker of one molecule in the substrate binding site of another, attenuating the chaperone function of oligomeric BiP. Native gel electrophoresis revealed a rapidly-modulated reciprocal relationship between the burden of unfolded proteins and BiP oligomers and slower equilibration between oligomers and inactive, covalently-modified BiP. Lumenal ER calcium depletion caused rapid oligomerization of mammalian BiP and a coincidental diminution in substrate binding, pointing to the relative inertness of the oligomers. Thus, equilibration between inactive oligomers and active monomeric BiP is poised to buffer fluctuations in ER unfolded protein load on a rapid timescale attainable neither by inter-conversion of active and covalently-modified BiP nor by the conventional unfolded protein response.
    eLife Sciences 10/2015; 4. DOI:10.7554/eLife.08961 · 9.32 Impact Factor
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    • "HSPs have been extensively utilized as biosensors to monitor environmental stress. They are very sensitive to, and altered even at sub-lethal doses of contaminants (Mayer and Bukau, 2005). HSPs function as intra-cellular chaperones that play important roles in protein folding (Mayer and Bukau, 2005; Mayer, 2013). "
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