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Abstract
A fundamental role of the Hsp90-Cdc37 chaperone system in mediating maturation of protein kinase clients and supporting kinase functional activity is essential for the integrity and viability of signaling pathways involved in cell cycle control and organism development. Despite significant advances in understanding structure and function of molecular chaperones, the molecular mechanisms and guiding principles of kinase recruitment to the chaperone system are lacking quantitative characterization. Structural and thermodynamic characterization of Hsp90-Cdc37 binding with protein kinase clients by modern experimental techniques is highly challenging, owing to a transient nature of chaperone-mediated interactions. In this work, we used experimentally-guided protein docking to probe the allosteric nature of the Hsp90-Cdc37 binding with the cyclin-dependent kinase 4 (Cdk4) kinase clients. The results of docking simulations suggest that the kinase recognition and recruitment to the chaperone system may be primarily determined by Cdc37 targeting of the N-terminal kinase lobe. The interactions of Hsp90 with the C-terminal kinase lobe may provide additional “molecular brakes” that can lock (or unlock) kinase from the system during client loading (release) stages. The results of this study support a central role of the Cdc37 chaperone in recognition and recruitment of the kinase clients. Structural analysis may have useful implications in developing strategies for allosteric inhibition of protein kinases by targeting the Hsp90-Cdc37 chaperone machinery.
Highlights
Molecular chaperones are essential proteins that have evolved to assist and facilitate conformational development, folding and stability of a diverse repertoire of protein clients inside the cell, including a wide range of protein kinases [1,2,3,4,5,6,7,8,9,10]
The results of docking simulations suggest that the kinase recognition and recruitment to the chaperone system may be primarily determined by Cell division cycle protein 37 (Cdc37) targeting of the N-terminal kinase lobe
Structural analysis and comparison of dynamic and interaction preferences of the kinase clients may help to clarify whether the αC-β4/αC-helix motif has a universal functional role that could be tailored for general recognition of kinase folds and specific regulatory functions
Summary
Molecular chaperones are essential proteins that have evolved to assist and facilitate conformational development, folding and stability of a diverse repertoire of protein clients inside the cell, including a wide range of protein kinases [1,2,3,4,5,6,7,8,9,10]. The crystal structure of the human Cdc construct (residues 148–348) in the complex with the yeast Hsp90-NTD has revealed a Cdc dimer bound to the “lid” segment of the Hsp90-NTD and intruding into the Hsp nucleotide binding pocket [50] These interactions formed between the middle domain of Cdc and the Hsp90-NTD can inhibit the ATPase activity of Hsp by preventing dimerization and disrupting the Hsp ATPase cycle [50,51]. SAXS studies have suggested a model in which a Cdc dimer would bind to both N-terminal domains of the Hsp dimer, causing a contraction of the apo-Hsp and preventing closure of the nucleotide site needed for the ATPase hydrolysis [49] According to this mechanism, a Cdc37-mediated arrest of the Hsp90-ATPase cycle in a specific functional form of Hsp would allow for a dynamic loading and release of kinase clients to the Hsp machinery [49,50,51]. The results of docking simulations suggest that the kinase recognition and recruitment to the chaperone system may be primarily determined by Cdc targeting of the N-terminal kinase lobe
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