Disease Variants of FGFR3 Reveal Molecular Basis for the Recognition and Additional Roles for Cdc37 in Hsp90
Tom D Bunney1, Alison J Inglis2, Domenico Sanfelice1
1Institute of Structural and Molecular Biology, Division of Biosciences, University College London, Gower St, London WC1E 6BT, UK.
Abstract:
Receptor tyrosine kinase FGFR3 is involved in many signaling networks and is frequently mutated in developmental disorders and cancer. The Hsp90/Cdc37 chaperone system is essential for function of normal and neoplastic cells. Here we uncover the mechanistic inter-relationships between these proteins by combining approaches including NMR, HDX-MS, and SAXS. We show that several disease-linked mutations convert FGFR3 to a stronger client, where the determinant underpinning client strength involves an allosteric network through the N-lobe and at the lobe interface. We determine the architecture of the client kinase/Cdc37 complex and demonstrate, together with site-specific information, that binding of Cdc37 to unrelated kinases induces a common, extensive conformational remodeling of the kinase N-lobe, beyond localized changes and interactions within the binary complex. As further shown for FGFR3, this processing by Cdc37 deactivates the kinase and presents it, in a specific orientation established in the complex, for direct recognition by Hsp90.
Insights
Mutations in FGFR3 (Fibroblast Growth Factor Receptor 3) can make it a stronger client for the Hsp90/Cdc37 chaperone system. This interaction deactivates FGFR3 and prepares it for Hsp90 binding.
Area of Science:
- Molecular Biology
- Biochemistry
- Structural Biology
Background:
- Receptor tyrosine kinase FGFR3 is implicated in developmental disorders and cancer.
- The Hsp90/Cdc37 chaperone system is crucial for cellular function in both normal and neoplastic cells.
Purpose of the Study:
- To elucidate the mechanistic interplay between FGFR3 and the Hsp90/Cdc37 chaperone system.
- To understand how disease-linked mutations in FGFR3 affect its interaction with chaperones.
Main Methods:
- Nuclear Magnetic Resonance (NMR) spectroscopy
- Hydrogen-Deuterium Exchange Mass Spectrometry (HDX-MS)
- Small-Angle X-ray Scattering (SAXS)
Main Results:
- Disease-associated FGFR3 mutations enhance its client strength for the Hsp90/Cdc37 system.
- Cdc37 binding induces significant conformational changes in the kinase N-lobe of unrelated kinases.
- Cdc37 binding deactivates FGFR3 and orients it for Hsp90 recognition.
Conclusions:
- The study reveals a common mechanism of kinase processing by Cdc37, involving extensive N-lobe remodeling.
- An allosteric network in FGFR3, spanning the N-lobe and lobe interface, dictates client strength.
- This work provides mechanistic insights into chaperone-mediated regulation of receptor tyrosine kinases.
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