Abstract
Allosteric interactions of the molecular chaperone Hsp90 with a large cohort of cochaperones and client proteins allow for molecular communication and event coupling in signal transduction networks. The integration of cochaperones into the Hsp90 system is driven by the regulatory mechanisms that modulate the progression of the ATPase cycle and control the recruitment of the Hsp90 clientele. In this work, we report the results of computational modeling of allosteric regulation in the Hsp90 complexes with the cochaperones p23 and Aha1. By integrating protein docking, biophysical simulations, modeling of allosteric communications, protein structure network analysis and the energy landscape theory we have investigated dynamics and stability of the Hsp90-p23 and Hsp90-Aha1 interactions in direct comparison with the extensive body of structural and functional experiments. The results have revealed that functional dynamics and allosteric interactions of Hsp90 can be selectively modulated by these cochaperones via specific targeting of the regulatory hinge regions that could restrict collective motions and stabilize specific chaperone conformations. The protein structure network parameters have quantified the effects of cochaperones on conformational stability of the Hsp90 complexes and identified dynamically stable communities of residues that can contribute to the strengthening of allosteric interactions. According to our results, p23-mediated changes in the Hsp90 interactions may provide “molecular brakes” that could slow down an efficient transmission of the inter-domain allosteric signals, consistent with the functional role of p23 in partially inhibiting the ATPase cycle. Unlike p23, Aha1-mediated acceleration of the Hsp90-ATPase cycle may be achieved via modulation of the equilibrium motions that facilitate allosteric changes favoring a closed dimerized form of Hsp90. The results of our study have shown that Aha1 and p23 can modulate the Hsp90-ATPase activity and direct the chaperone cycle by exerting the precise control over structural stability, global movements and allosteric communications in Hsp90.
Highlights
Molecular chaperones are essential proteins that have evolved to assist and facilitate conformational development, folding and stability of a diverse repertoire of proteins inside the cell [1,2,3,4,5,6,7]
Functional dynamics and allosteric interactions of Hsp90 can be selectively modulated by these co-chaperones
We have found that p23mediated changes in the dynamic signature of Hsp90 are associated with stabilization of the Hsp90-N dimer interactions that are supported by the consolidation of the N-M contacts
Summary
Molecular chaperones are essential proteins that have evolved to assist and facilitate conformational development, folding and stability of a diverse repertoire of proteins inside the cell [1,2,3,4,5,6,7]. Similarity of collective motions may reflect a common topography of the allosteric network, whereas selection and activation of specific communication routes seems to be cochaperone-dependent and potentially function as a ‘‘relay switch’’ of the conformational equilibrium This distinctive dynamic signature of the Hsp90-p23 complex may be associated with the functional role of p23 that partially inhibits the ATPase cycle via trapping Hsp in a hydrolysis-competent state, which is likely to regulate the residence time of ‘‘highly demanding’’ clients favoring this specific form [19,20,21,22,23]. Allosteric protein systems and macromolecular assemblies with different internal architecture and structural folds may use different mechanisms or their combinations in order to efficiently transmit signals between distant sites
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