Abstract
Post-translational modifications (PTMs) represent an important regulatory instrument that modulates structure, dynamics and function of proteins. The large number of PTM sites in the Hsp90 proteins that are scattered throughout different domains indicated that synchronization of multiple PTMs through a combinatorial code can be invoked as an important mechanism to orchestrate diverse chaperone functions and recognize multiple client proteins. In this study, we have combined structural and coevolutionary analysis with molecular simulations and perturbation response scanning analysis of the Hsp90 structures to characterize functional role of PTM sites in allosteric regulation. The results reveal a small group of conserved PTMs that act as global mediators of collective dynamics and allosteric communications in the Hsp90 structures, while the majority of flexible PTM sites serve as sensors and carriers of the allosteric structural changes. This study provides a comprehensive structural, dynamic and network analysis of PTM sites across Hsp90 proteins, identifying specific role of regulatory PTM hotspots in the allosteric mechanism of the Hsp90 cycle. We argue that plasticity of a combinatorial PTM code in the Hsp90 may be enacted through allosteric coupling between effector and sensor PTM residues, which would allow for timely response to structural requirements of multiple modified enzymes.
Highlights
Sets, another study identified motifs enriched by pairs of known Post-translational modifications (PTMs) sites, including three combinations of PTM types: phosphorylation-acetylation, phosphorylation-SUMOylation, and phosphorylation-phosphorylation[9]
The results reveal conserved PTMs that act as central mediators and regulatory hotspots of allosteric signaling in the Hsp[90] proteins, while the majority of PTM sites serve as sensors and transmitters of the allosteric signal in collectively moving Hasp[90] regions
To systematically characterize PTM sites in the Hsp[90] chaperone proteins, we surveyed PhosphoSitePlus database that contains over 330,000 non-redundant PTMs, with 95% of the sites obtained from mass spectrometry experiments[3]
Summary
Sets, another study identified motifs enriched by pairs of known PTM sites, including three combinations of PTM types: phosphorylation-acetylation, phosphorylation-SUMOylation, and phosphorylation-phosphorylation[9]. A quantitative analysis of phosphorylation sites in yeast Hsp[82] revealed their functional role as molecular switches of conformational equilibrium and allosteric interactions as phosphorylation-mimicking chaperone variants in the Hsp82-MD regions (S379E, S485E) and Hsp82-CTD (S602E, S604E) featured the markedly reduced rates of ATP hydrolysis[38]. We have combined evolutionary analysis, all-atom and coarse-grained simulations of the Hsp[90] proteins with the network analysis of residue interactions and perturbation response scanning (PRS) approach to probe allosteric mechanisms and quantify functional roles of PTM sites in allosteric regulation of the molecular chaperone. This study provides a comprehensive structural, dynamic and network analysis of PTM sites across Hsp[90] proteins, identifying specific role of regulatory PTM hotspots in modulating of allosteric interactions and signal transmission in the Hsp[90] structures. By combining PRS analysis of functional centers and network-based modeling of allosteric communication pathways, we determine key regulatory PTM sites in the Hsp[90] chaperones can serve as gate-keepers and conformational switches of chaperone functions and interactions
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