Research

Scientists from the Rocasolano Institute and the Max Planck Institute in Göttingen, Germany have published a comprehensive study describing the malignant action of an Hsp90 co-chaperone in Alzheimer's pathogenesis

The highly-abundant, highly-conserved molecular chaperone Hsp90 is critical for the maintenance of cellular homeostasis and represents a promising drug target. This chaperone presents a strikingly high “client“ promiscuity and specificity, which are tightly controled by a host of so-called co-chaperones. Despite increasing knowledge on the structure of different Hsp90 complexes, the molecular basis of client recognition and pro-folding by Hsp90/co-chaperone complexes remains unknown, precluding the design of more potent/specific therapeutic compounds against this molecule in cancer and neurodegenerative diseases.

This study reports the solution structure and binding mechanism of human full-length Hsp90 in complex with the PPIase co-chaperone FKBP51, as well as the 280 kDa Hsp90/FKBP51 complex bound to the Alzheimer’s disease-related protein Tau. FKBP51, which is upregulated in aged and Alzheimer’s brain, synergizes with Hsp90 to promote Tau toxic oligomers in vivo. This study also shows that, within the ternary Hsp90/FKBP51/Tau complex, Hsp90 serves as a passive scaffold that traps the PPIase and nucleates multiple conformations of Tau’s proline rich region next to the PPIase catalytic pocket. Thus, the study defines a conceptual model for dynamic Hsp90/co-chaperone/client recognition and provides a plausible mechanisitic explanation for the pro-toxic role of this complex in Alzheimer’s disease.

This work was first-authored by Javier Oroz, who recently joined the “Rocasolano” Physical-Chemistry Institute and performed this study during his postdoc in Prof. Markus Zweckstetter’s group at Max Planck Institute for Biophysical Chemistry (Göttingen, Germany).

Oroz, J., Chang, B.J., Wysoczanski, P., Lee, C.T., Pérez-Lara, Á., Chakraborty, P., Hofele, R.V., Baker, J.D., Blair, L.J., Biernat, J., Urlaub, H., Mandelkow, E., Dickey, C.A., Zweckstetter, M. Structure and pro-toxic mechanism of the human Hsp90/PPIase/Tau complex. Nature Communications (2018) 9 (1): 4532. doi: 10.1038/s41467-018-06880-0.

(PIE DE FIGURA):This study describes the structure of Tau ensemble of conformations (in yellow and red) bound to Hsp90/FKBP51 complex (in grey and blue, respectively). FKBP51 induces the death of CA3 hippocampal neurons through the aggregation of Tau.