Abstract
Catalysis of ADP-ATP exchange by nucleotide exchange factors (NEFs) is central to the activity of Hsp70 molecular chaperones. Yet, the mechanism of interaction of this family of chaperones with NEFs is not well understood in the context of the sequence evolution and structural dynamics of Hsp70 ATPase domains. We studied the interactions of Hsp70 ATPase domains with four different NEFs on the basis of the evolutionary trace and co-evolution of the ATPase domain sequence, combined with elastic network modeling of the collective dynamics of the complexes. Our study reveals a subtle balance between the intrinsic (to the ATPase domain) and specific (to interactions with NEFs) mechanisms shared by the four complexes. Two classes of key residues are distinguished in the Hsp70 ATPase domain: (i) highly conserved residues, involved in nucleotide binding, which mediate, via a global hinge-bending, the ATPase domain opening irrespective of NEF binding, and (ii) not-conserved but co-evolved and highly mobile residues, engaged in specific interactions with NEFs (e.g., N57, R258, R262, E283, D285). The observed interplay between these respective intrinsic (pre-existing, structure-encoded) and specific (co-evolved, sequence-dependent) interactions provides us with insights into the allosteric dynamics and functional evolution of the modular Hsp70 ATPase domain.
Highlights
Calculations repeated with nucleotide exchange factors (NEFs)-bound ATPase domains reveal how the open form of the ATPase domain is stabilized in order to facilitate ADP release, which is enabled by the intrinsic mobility of the NEF-binding regions
The results indicate that the NEF-bound form of the heat shock protein 70 (Hsp70) ATPase domain closely maintains the intrinsic dynamics accessible to its unbound form, i.e., the loci of peaks and minima remain practically unchanged; binding of a NEF alters the relative distribution of mobilities: in particular, a reduction is observed in the mobility of subdomain IIB
In order to examine quantitatively to what extent the observed reconfiguration is an intrinsic property of the Hsp70 ATPase domain, we focused on the softest motions predicted by the anisotropic network model (ANM)
Summary
A subtle balance exists between structureencoded mechanical properties and sequence-encoded specific properties, and this balance must be evolutionarily optimized to achieve precise functioning. The interplay between these two effects becomes important in the case of a number of proteins or domains that play a modular role in a variety of biomolecular interactions. The ATPase domain ( called nucleotide-binding domain) of the Hsp family of proteins is a typical example This domain plays a critical role in regulating the activities of these molecular chaperones, which, in turn, promote accurate folding, and prevent unwanted aggregation by either unfolding and refolding misfolded proteins or regulating their intracellular trafficking to the protein degradation machinery [3,4,5]
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