Structural representation of the key PKC residues involved in Hsp70/Cdc37 binding: the C-terminal PXXP motif (in dark red) and determinants in the αE-helix of the catalytic domain (yellow).
Protein kinases are major regulators of key integrative processes such as cell growth, proliferation, and apoptosis. For many protein kinases, an important regulatory step is the maturation and processing of the polypeptide, which usually requires input from a complex containing the chaperone proteins Hsp90 and Cdc37. These chaperones ensure that the kinase attains an appropriate conformation during synthesis, activation, and deactivation. Accordingly, understanding how Hsp90/Cdc37 interact with their client kinases is important. In this Paper of the Week, Christine Gould and colleagues identify a critical binding motif conserved in AGC kinases (a large kinase family that includes protein kinases A, G, and C) necessary for Hsp90/Cdc37 binding and the maturation of several protein kinase C (PKC) proteins. They show that this PXXP motif (located on the C-terminal tail), coupled with additional sequence determinants within the PKC kinase core, is essential for Hsp90/Cdc37 binding, an event that is required for subsequent processing of PKC via phosphorylation. Given the conservation of the PXXP motif in the AGC family and the importance of Hsp90/Cdc37 for the maturation of other protein kinase families (e.g. the Rafs), these findings reveal an important and potentially widespread mechanism controlling chaperone binding.
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Christine M. Gould
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Published online: February 20, 2009
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♦See referenced article, J. Biol. Chem. 2009, 284, 4921-4935
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© 2009 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.
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