Structural Properties of chaperone substrates

Hsp90 chaperones seem to be dedicated for specific sets of substrates. Just over 100 Hsp90 substrates are identified to date, of which 45% are kinases and 15% transcription factors. The structural reasons for this selection are unclear, neither what they have in common nor why this subset of proteins requires the special attention of Hsp90.

We are characterizing the stability with biochemical and biophysical methods, in particular fluorescence- and NMR spectroscopy. We found earlier that the tumour suppressor p53 is unfolded when bound to Hsp90. We are now analysing to which extent this is a general principle.

• STRUCTURE OF A CHAPERONE SUBSTRATE
  Hsp90-bound p53 core domain is predominantly unfolded, shown by NMR-spectroscopy using CRINEPT-TROSY technique. Two dimensional NMR spectra of 15N-labelled p53 core domain bound to unlabelled Hsp90 give signals only for p53 (blue). The spectra are similar to that of p53 core domain unfolded in urea, which shows only random coil signal (orange). In contrast, the spectrum of folded p53 has the well spread signal pattern of a folded protein (green)
  (taken from Rüdiger S, Freund SMV, Veprintsev DB & Fersht AR CRINEPT-TROSY NMR reveals p53 core domain bound in an unfolded form to the chaperone Hsp90. PNAS; 2002; 99:11085-90. pdf)

• Molecular mechanisms of chaperone interaction with their substrates.
  - Substrate recognition of molecular chaperones
  - Mechanisms of chaperone-assisted protein folding
  - Structural properties of chaperone substrates

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