PLoS Biol 17(7):Īcademic Editor: Jun-Yi Leu, Academia Sinica, TAIWAN (2019) Global proteomic analyses define an environmentally contingent Hsp90 interactome and reveal chaperone-dependent regulation of stress granule proteins and the R2TP complex in a fungal pathogen. This study provides a global view of the Hsp90 interactome in a fungal pathogen, demonstrates the dynamic role of Hsp90 in response to environmental perturbations, and highlights a novel connection between Hsp90 and the regulation of mRNA-associated protein granules.Ĭitation: O’Meara TR, O’Meara MJ, Polvi EJ, Pourhaghighi MR, Liston SD, Lin Z-Y, et al. We also describe novel roles for Hsp90 in regulating posttranslational modification of the Rvb1-Rvb2-Tah1-Pih1 (R2TP) complex and the formation of protein aggregates in response to thermal stress. We performed the first analysis of the Hsp90 interactome upon antifungal drug stress and demonstrated that Hsp90 stabilizes processing body (P-body) and stress granule proteins that contribute to drug tolerance. In parallel, we performed affinity purification coupled to mass spectrometry to define physical interacting partners for Hsp90 and the Hsp90 co-chaperones and identified 164 Hsp90-interacting proteins, including 111 that are specific to the pathogen. To address this challenge, we applied a novel biochemical fractionation and quantitative proteomic approach to examine alterations to the proteome upon perturbation of Hsp90 in a leading human fungal pathogen, Candida albicans. This is a pressing challenge for fungal pathogens, for which Hsp90 is a key regulator of stress tolerance, drug resistance, and virulence traits. Currently, there are no methods to accurately predict Hsp90 interactors and there has been considerable network rewiring over evolutionary time, necessitating experimental approaches to define the Hsp90 network in the species of interest. These interactions include client proteins, which physically interact with Hsp90 and depend on the chaperone for stability or function, as well as co-chaperones and partner proteins that modulate chaperone function. As a central hub of protein interaction networks, Hsp90 engages with hundreds of protein–protein interactions within eukaryotic cells. Cooperation of different chaperone machineries creates a synergistic network of folding helpers in the cell, which allows to maintain protein homeostasis under conditions nonpermissive for spontaneous folding.Hsp90 is a conserved molecular chaperone that assists in the folding and function of diverse cellular regulators, with a profound impact on biology, disease, and evolution. Therefore, the ATP-independent chaperones can be regarded as efficient 'holding' components. sHsps, SecB) the energy-dependent step is performed by another chaperone (Hsp70, SecA). While for ATP-dependent chaperones binding sites for nucleotide and protein are found in one protein, in the case of ATP-independent chaperones (e. Interestingly, the ATPase activity which is the key determinant for functional cycles is tightly regulated by a set of co-chaperones. GroEL, Hsp70, Hsp90) leads to sometimes large conformational changes in the chaperone which allow to shift between high- and low-affinity states for substrate proteins. Nucleotide binding to ATP-dependent chaperones (e.g. A landmark feature of molecular chaperones is the involvement of energy-dependent reactions in the folding process. The underlying functional principles of the different chaperone classes are beginning to be understood. They share the ability to recognize and bind nonnative proteins thus preventing unspecific aggregation. Chaperones are a functionally related group of proteins assisting protein folding in the cell under physiological and stress conditions.
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