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The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding.

Publication ,  Journal Article
Woodford, MR; Dunn, DM; Blanden, AR; Capriotti, D; Loiselle, D; Prodromou, C; Panaretou, B; Hughes, PF; Smith, A; Ackerman, W; Haystead, TA ...
Published in: Nat Commun
June 29, 2016

Heat shock protein-90 (Hsp90) is an essential molecular chaperone in eukaryotes involved in maintaining the stability and activity of numerous signalling proteins, also known as clients. Hsp90 ATPase activity is essential for its chaperone function and it is regulated by co-chaperones. Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. FNIPs decelerate the chaperone cycle, facilitating FLCN interaction with Hsp90, consequently ensuring FLCN stability. FNIPs compete with the activating co-chaperone Aha1 for binding to Hsp90, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins. Lastly, downregulation of FNIPs desensitizes cancer cells to Hsp90 inhibitors, whereas FNIPs overexpression in renal tumours compared with adjacent normal tissues correlates with enhanced binding of Hsp90 to its inhibitors. Our findings suggest that FNIPs expression can potentially serve as a predictive indicator of tumour response to Hsp90 inhibitors.

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Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

June 29, 2016

Volume

7

Start / End Page

12037

Location

England

Related Subject Headings

  • Tumor Suppressor Proteins
  • Proto-Oncogene Proteins
  • Molecular Chaperones
  • Intracellular Signaling Peptides and Proteins
  • Humans
  • HSP90 Heat-Shock Proteins
  • Gene Expression Regulation, Neoplastic
  • Cell Line, Tumor
  • Carrier Proteins
  • Carcinoma, Renal Cell
 

Citation

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Woodford, M. R., Dunn, D. M., Blanden, A. R., Capriotti, D., Loiselle, D., Prodromou, C., … Mollapour, M. (2016). The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding. Nat Commun, 7, 12037. https://doi.org/10.1038/ncomms12037
Woodford, Mark R., Diana M. Dunn, Adam R. Blanden, Dante Capriotti, David Loiselle, Chrisostomos Prodromou, Barry Panaretou, et al. “The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding.Nat Commun 7 (June 29, 2016): 12037. https://doi.org/10.1038/ncomms12037.
Woodford MR, Dunn DM, Blanden AR, Capriotti D, Loiselle D, Prodromou C, et al. The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding. Nat Commun. 2016 Jun 29;7:12037.
Woodford, Mark R., et al. “The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding.Nat Commun, vol. 7, June 2016, p. 12037. Pubmed, doi:10.1038/ncomms12037.
Woodford MR, Dunn DM, Blanden AR, Capriotti D, Loiselle D, Prodromou C, Panaretou B, Hughes PF, Smith A, Ackerman W, Haystead TA, Loh SN, Bourboulia D, Schmidt LS, Marston Linehan W, Bratslavsky G, Mollapour M. The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding. Nat Commun. 2016 Jun 29;7:12037.

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

June 29, 2016

Volume

7

Start / End Page

12037

Location

England

Related Subject Headings

  • Tumor Suppressor Proteins
  • Proto-Oncogene Proteins
  • Molecular Chaperones
  • Intracellular Signaling Peptides and Proteins
  • Humans
  • HSP90 Heat-Shock Proteins
  • Gene Expression Regulation, Neoplastic
  • Cell Line, Tumor
  • Carrier Proteins
  • Carcinoma, Renal Cell