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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) (KAR id:66869)

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: Divisions > Division of Natural Sciences > Biosciences
Depositing User: Gary Thompson
Date Deposited: 30 Apr 2018 11:00 UTC
Last Modified: 09 Dec 2022 06:44 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/66869 (The current URI for this page, for reference purposes)

University of Kent Author Information

Thompson, Gary S..

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