To name just a few of their functions in bacteria, Hsp70s assist de-novo-folding of proteins interacting with nascent chains already at the ribosome ( Deuerling et al., 1999 Calloni et al., 2012), prevent aggregation of stress denatured proteins ( Mogk et al., 1999), and solubilize protein aggregates ( Goloubinoff et al., 1999) ( Figure 1A). The ATP-dependent 70 kDa heat shock proteins (Hsp70s) are without doubt the most versatile of all chaperones and involved in many diverse folding processes in the cell ( Meimaridou et al., 2009 Clerico et al., 2015). In this review I will discuss advances in the understanding of the molecular mechanism of the Hsp70 chaperone machinery focusing mostly on the bacterial Hsp70 DnaK and will compare the two other prokaryotic Hsp70s HscA and HscC with DnaK. Third, Hsp70s are targeted to their clients by a large number of cochaperones of the J-domain protein (JDP) family and the lifetime of the Hsp70-client complex is regulated by nucleotide exchange factors (NEF). Second, Hsp70 chaperones switch in a nucleotide-controlled manner between a state of low affinity for client proteins and a state of high affinity for clients. First, Hsp70s bind to short degenerate sequence motifs within their client proteins. Three mechanistic properties of Hsp70s are the basis for their high versatility. Through a multitude of functions Hsp70s are involved in many cellular control circuits for maintaining protein homeostasis and have been recognized as key factors for cell survival. None of the other main chaperone families (Tig, GroELS, HtpG, IbpA/B, ClpB) have been assigned with a comparable range of functions. The ATP-dependent Hsp70s are evolutionary conserved molecular chaperones that constitute central hubs of the cellular protein quality surveillance network. Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH-Alliance, Heidelberg, Germany.(2006) Self-association and chaperone activity of Hsp27 are thermally activated. (2000) Differential regulation of HSP27 oligomerization in tumor cells grown in vitro and in vivo. M., Paul, C., Fromentin, A., Hilpert, S., Arrigo, A. (2005) Mechanism of chaperone function in small heat shock proteins: dissociation of the HSP27 oligomer is required for recognition and binding of destabilized T4 lysozyme. (1997) Binding of non-native protein to Hsp25 during heat shock creates a reservoir of folding intermediates for reactivation. Ehrnsperger, M., Gräber, S., Gaestel, M., Buchner, J.(1999) In vivo chaperone activity of heat shock protein 70 and thermotolerance. (1992) The transport of proteins into the nucleus requires the 70-kilodalton heat shock protein or its cytosolic cognate. (2006) Hsp70 chaperones accelerate protein translocation and the unfolding of stable protein aggregates by entropic pulling. De Los Rios, P., Ben-Zvi, A., Slutsky, O., Azem, A., Goloubinoff, P.(1990) Interaction of Hsp 70 with newly synthesized proteins: implications for protein folding and assembly. Beckmann, R.P., Mizzen, L.E., Welch, W.Chromatin assembly and transcription in eggs and oocytes of Xenopus laevis.
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