Abstract
The interaction between the Heat Shock Proteins 70 and 40 is at the core of the ATPase regulation of the chaperone machinery that maintains protein homeostasis. However, the structural details of the interaction remain elusive and contrasting models have been proposed for the transient Hsp70/Hsp40 complexes. Here we combine molecular simulations based on both coarse-grained and atomistic models with coevolutionary sequence analysis to shed light on this problem by focusing on the bacterial DnaK/DnaJ system. The integration of these complementary approaches resulted in a novel structural model that rationalizes previous experimental observations. We identify an evolutionarily conserved interaction surface formed by helix II of the DnaJ J-domain and a structurally contiguous region of DnaK, involving lobe IIA of the nucleotide binding domain, the inter-domain linker, and the β-basket of the substrate binding domain.
Highlights
The 70 kDa and 40 kDa Heat Shock Proteins (Hsp70/Hsp40) form the core of a chaperone machinery that plays essential roles in proteostasis and proteolytic pathways (Daugaard et al, 2007; Hartl et al, 2011; Mayer, 2013)
The nature of the bound nucleotide induces dramatically different conformations of Hsp70/40 families (Hsp70): in the ADP-bound state, the two domains are mostly detached and behave almost independently (Bertelsen et al, 2009), whereas in the ATP-bound state, the substrate binding domain (SBD) splits into two sub-domains that dock onto the nucleotide binding domain (NBD) (Kityk et al, 2012; Qi et al, 2013)
We took advantage of this approach and of the availability of high-resolution structures of the individual binding partners to investigate complexes formed by the J-domain of E. coli DnaJ (JD) with the DnaK NBD, both in its ADP- and ATPbound conformations (NBD(ADP), NBD(ATP))
Summary
The 70 kDa and 40 kDa Heat Shock Proteins (Hsp70/Hsp40) form the core of a chaperone machinery that plays essential roles in proteostasis and proteolytic pathways (Daugaard et al, 2007; Hartl et al, 2011; Mayer, 2013). Members of the Hsp family are composed of two domains, connected by a flexible linker: the N-terminal nucleotide binding domain (NBD) binds and hydrolyzes ATP, whereas the C-terminal substrate binding domain (SBD) interacts with client proteins (Zuiderweg et al, 2013). Nucleotide hydrolysis and exchange induce large-scale conformational dynamics that regulate the chaperone interaction with client proteins (Mayer, 2013)
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