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Surface charge and hydrophobicity determine ErbB2 binding to the Hsp90 chaperone complex

Nature Structural & Molecular Biology volume 12, pages 120–126 (2005)Cite this article

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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Figure 1: Sensitivities of ErbB2 deletion mutants to GA-induced degradation and their binding to Hsp90.
Figure 2: ErbB2-5M is incapable of binding the Hsp90 complex and is resistant to GA-induced degradation.
Figure 3: Surface features of the kinase domains of the wild-type and mutant ErbB1 and ErbB2 proteins.
Figure 4: Single point mutations in the chaperone-interacting loop alter GA sensitivity and binding of the Hsp90 complex to both ErbB1 and ErbB2.
Figure 5: Nascent and mature ErbB2-5M proteins show disparate GA sensitivities.

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Author notes

  1. Wanping Xu and Xitong Yuan: These authors contributed equally to this work.

Authors and Affiliations

  1. Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Rockville, 20850, Maryland, USA

    Wanping Xu, Xitong Yuan, Edward Mimnaugh, Monica Marcu & Len Neckers

  2. Center for Molecular Modeling, Center for Information Technology, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Zhexin Xiang

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  1. Wanping Xu
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Correspondence to Len Neckers.

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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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