Skip to main content

Disease Variants of FGFR3 Reveal Molecular Basis for the Recognition and Additional Roles for Cdc37 in Hsp90 Chaperone System

Bunney, Tom D., Inglis, Alison J., Sanfelice, Domenico, Farrell, Brendan, Kerr, Christopher J., Thompson, Gary S., Masson, Glenn R., Thiyagarajan, Nethaji, Svergun, Dmitri I., Williams, Roger L., and others. (2018) Disease Variants of FGFR3 Reveal Molecular Basis for the Recognition and Additional Roles for Cdc37 in Hsp90 Chaperone System. Structure, 26 (3). pp. 446-458. ISSN 0969-2126. (doi:10.1016/j.str.2018.01.016)

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 pro- teins 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 architec- ture of the client kinase/Cdc37 complex and dem on- strate, together with site-speci?c information, that binding of Cdc37 to unrelated kinases induces a common, extensive conformational remodeling of the kinase N-lobe, beyond localized changes and in- teractions within the binary complex. As further shown for FGFR3, this processing by Cdc37 deacti- vates the kinase and presents it, in a speci ?c orienta- tion established in the complex, for direct recognition by Hsp90.

Item Type: Article
DOI/Identification number: 10.1016/j.str.2018.01.016
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: G. Thompson
Date Deposited: 30 Apr 2018 11:00 UTC
Last Modified: 29 May 2019 20:30 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/66869 (The current URI for this page, for reference purposes)
  • Depositors only (login required):

Downloads

Downloads per month over past year