Allosteric Regulation of the Hsp90 Dynamics and Stability by Client Recruiter Cochaperones: Protein Structure Network Modeling

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.

Four-colour FRET reveals directionality in the Hsp90 multicomponent machinery

“…Our new findings on the function of cochaperones are complementary to previous explanations, which focused on how cochaperones affect the conformational equilibrium in Hsp90's ATPase cycle 24 . Our study hints towards a more complicated mutual interaction between Hsp90 and its cochaperones, which is supported by molecular dynamics simulations 43 . On the basis of experiments, such a mutual interaction has already been suggested for E. coli Hsp90 (HtpG) and a model substrate protein 44 .…”

Computational Studies of Allosteric Regulation in the Hsp90 Molecular Chaperone: From Functional Dynamics and Protein Structure Networks to Allosteric Communications and Targeted Anti‐Cancer Modulators

“…[160] Dynamic signatures of the Hsp90 complexes with client recruiter cochaperones Cdc37, Sgt1, and Rar1 were studied in recent subsequent work. [161] Consistent with the experiments, it has been determined that targeted reorganization of the lid dynamics is a unifying characteristic of the client recruiter cochaperones. Protein network analysis of the Hsp90Àcochaperone principal motions has identified structurally stable interaction communities, interfacial hubs and key mediating residues of allosteric communication pathways.…”

Singular value decomposition for the correlation of atomic fluctuations with arbitrary angle

“…Different from the sequence‐based methods, the conformation‐based methods determine the correlated residues from protein conformations. Sometimes these are derived from the native contact map of a single native structure aided by graph theory, but are more frequently determined by examining the conformation ensemble. The ensemble character of protein allostery implies that less populated states can significantly affect protein function .…”

“…structure aided by graph theory, [21][22][23][24][25] but are more frequently determined by examining the conformation ensemble. The ensemble character of protein allostery implies that less populated states can significantly affect protein function.…”