Abstract
The molecular chaperone Hsp90 modulates the function of specific cell signaling proteins. Although targeting Hsp90 with the antibiotic inhibitor geldanamycin (GA) may be a promising approach for cancer treatment, little is known about the determinants of Hsp90 interaction with its client proteins. Here we identify a loop within the N lobe of the kinase domain of ErbB2 that determines Hsp90 binding. The amino acid sequence of the loop determines the electrostatic and hydrophobic character of the protein's surface, which in turn govern interaction with Hsp90. A point mutation within the loop that alters ErbB2 surface properties disrupts Hsp90 association and confers GA resistance. Notably, the immature ErbB2 point mutant remains sensitive to GA, suggesting that mature and nascent client kinases may use distinct motifs to interact with the Hsp90 chaperone complex.
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Supplementary information
Supplementary Fig. 1
Alignment of the amino acid sequence of ErbB1 and ErbB2 kinase domain regions. (PDF 383 kb)
Supplementary Fig. 2
Ribbon diagram of the superimposed kinase domains of ErbB1 and ErbB2. (PDF 1233 kb)
Supplementary Fig. 3
Structure of the M5 loop of ErbB1, ErbB2 and ErbB2-G778N, showing the two trapped water molecules. (PDF 948 kb)
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Xu, W., Yuan, X., Xiang, Z. et al. Surface charge and hydrophobicity determine ErbB2 binding to the Hsp90 chaperone complex. Nat Struct Mol Biol 12, 120–126 (2005). https://doi.org/10.1038/nsmb885
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DOI: https://doi.org/10.1038/nsmb885
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