Abstract
Hsp70s chaperone an amazing number and variety of cellular protein folding processes. Key to their versatility is the recognition of a short degenerate sequence motif, present in practically all polypeptides, and a bidirectional allosteric intramolecular regulation mechanism linking their N-terminal nucleotide binding domain (NBD) and their C-terminal polypeptide substrate binding domain (SBD). Through this interdomain communication ATP binding to the NBD and ATP hydrolysis control the affinity of the SBD for polypeptide substrates and substrate binding to the SBD triggers ATP hydrolysis. Genetic screens for defective variants of Hsp70s and systematic analysis of available structures of the isolated domains revealed some residues involved in allosteric control. Recent elucidation of the crystal structure of the Hsp70 homolog DnaK in the ATP bound open conformation as well as numerous NMR and mutagenesis studies bring us closer to an understanding of the communication between NBD and SBD. In this review we will discuss our current view of the allosteric control mechanism of Hsp70 chaperones.
Highlights
Hsp70s are involved in a large variety of cellular processes
Thereby they interact with substrate proteins that are in many different conformations: with completely extended polypeptides such as nascent chains at the ribosome (Deuerling and Bukau, 2004; Hartl et al, 2011) or during translocation into organelles (Neupert and Herrmann, 2007; Chacinska et al, 2009); with partially folded and misfolded conformations in late folding intermediates, or upon disaggregation and refolding of stress denatured proteins (Tyedmers et al, 2010); and with native regulatory proteins to control their activity and stability (Wegele et al, 2004), and while assisting oligomerization or disassembly of oligomeric structures
The crystal structure of DnaK in the ATP-bound open conformation was solved, which significantly broadened our knowledge about allostery in Hsp70s (Kityk et al, 2012; Qi et al, 2013)
Summary
Hsp70s are involved in a large variety of cellular processes. Thereby they interact with substrate proteins that are in many different conformations: with completely extended polypeptides such as nascent chains at the ribosome (Deuerling and Bukau, 2004; Hartl et al, 2011) or during translocation into organelles (Neupert and Herrmann, 2007; Chacinska et al, 2009); with partially folded and misfolded conformations in late folding intermediates, or upon disaggregation and refolding of stress denatured proteins (Tyedmers et al, 2010); and with native regulatory proteins to control their activity and stability (e.g., heat shock transcription factor σ32 in E. coli or transcription factors, receptors, and kinases in eukaryotes) (Wegele et al, 2004), and while assisting oligomerization or disassembly of oligomeric structures (e.g., clathrin, Sousa and Lafer, 2015). In contrast to ATP-independent chaperones, the affinity of Hsp70 for substrates is regulated by nucleotide, the substrate itself, the J-domain cochaperones and nucleotide exchange factors (Figure 1).
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