Abstract
The fundamental role of the Hsp90 chaperone in supporting functional activity of diverse protein clients is anchored by specific cochaperones. A family of immune sensing client proteins is delivered to the Hsp90 system with the aid of cochaperones Sgt1 and Rar1 that act cooperatively with Hsp90 to form allosterically regulated dynamic complexes. In this work, functional dynamics and protein structure network modeling are combined to dissect molecular mechanisms of Hsp90 regulation by the client recruiter cochaperones. Dynamic signatures of the Hsp90-cochaperone complexes are manifested in differential modulation of the conformational mobility in the Hsp90 lid motif. Consistent with the experiments, we have determined that targeted reorganization of the lid dynamics is a unifying characteristic of the client recruiter cochaperones. Protein network analysis of the essential conformational space of the Hsp90-cochaperone motions has identified structurally stable interaction communities, interfacial hubs and key mediating residues of allosteric communication pathways that act concertedly with the shifts in conformational equilibrium. The results have shown that client recruiter cochaperones can orchestrate global changes in the dynamics and stability of the interaction networks that could enhance the ATPase activity and assist in the client recruitment. The network analysis has recapitulated a broad range of structural and mutagenesis experiments, particularly clarifying the elusive role of Rar1 as a regulator of the Hsp90 interactions and a stability enhancer of the Hsp90-cochaperone complexes. Small-world organization of the interaction networks in the Hsp90 regulatory complexes gives rise to a strong correspondence between highly connected local interfacial hubs, global mediator residues of allosteric interactions and key functional hot spots of the Hsp90 activity. We have found that cochaperone-induced conformational changes in Hsp90 may be determined by specific interaction networks that can inhibit or promote progression of the ATPase cycle and thus control the recruitment of client proteins.
Highlights
Allosteric regulation and support of diverse protein clients underlie the fundamental role of the molecular chaperone Hsp90 in protein synthesis, refolding and degradation [1,2,3,4,5,6]
We compare distinctive networking profiles of the Hsp90-Cell division cycle protein 37 (Cdc37) and Hsp90-Sgt1-Rar1 complexes to illustrate how targeted modulation of the lid dynamics is coupled with specific interactions to inhibit or promote progression of the ATPase cycle
We carried out functional dynamics analysis of the Hsp90-Sgt1 and Hsp90-Sgt1-Rar1 complexes to (a) characterize cochaperone-specific modulation of the lid dynamics, and (b) understand how allosteric interactions with the lid motif may allow cochaperones to engineer global conformational changes and control the ATPase activity
Summary
Allosteric regulation and support of diverse protein clients underlie the fundamental role of the molecular chaperone Hsp in protein synthesis, refolding and degradation [1,2,3,4,5,6]. Conformational changes in the lid motif are coupled to the ATPase cycle, whereby upon ATP hydrolysis the lid flips away from the nucleotide site and concomitantly the Hsp dimer can adopt an open functional form. Central to the role of cochaperones is targeted modulation of the ATPase conformational cycle by turning stochastic conformational fluctuations of Hsp into precisely engineered progression of specific conformational states that are tailored to structural requirements of protein clients. The class of client recruiter cochaperones can contribute to the process of client selection and recognition, often by arresting the Hsp90-ATPase cycle in a particular conformational state in order to support activities of specific clients
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