Disease variants of FGFR3 reveal molecular basis for the recognition and additional roles for Cdc37 in Hsp90 Chaperone system

TY - JOUR

T1 - Disease variants of FGFR3 reveal molecular basis for the recognition and additional roles for Cdc37 in Hsp90 Chaperone system

AU - Bunney, Tom D.

AU - Inglis, Alison J.

AU - Sanfelice, Domenico

AU - Farrell, Brendan

AU - Kerr, Christopher J.

AU - Thompson, Gary S.

AU - Masson, Glenn R.

AU - Thiyagarajan, Nethaji

AU - Svergun, Dmitri I.

AU - Williams, Roger L.

AU - Breeze, Alexander L.

AU - Katan, Matilda

N1 - Funding Information: We thank A. Hussain, H. Patani, C. Pilotti, V. Dorovykh, N. Vajpai, H. Koss, D. Kent, and D. Bhalsod for supporting contributions. We are very grateful to C. Vaughan and B. Wallace for extremely helpful discussions. We acknowledge the use of the ISMB Biophysics Center and the support of T. Daviter. The M.K. laboratory is supported by Cancer Research UK ( A16567 ). A.L.B. acknowledges access to the Astbury BioStructure Laboratory BioNMR Facility (University of Leeds), which was funded by the Wellcome Trust (grant number 104920/Z/14/Z ) and the University of Leeds , and thanks A. Kalverda for NMR technical assistance. B.F. is supported by a Wellcome Trust studentship ( 109155/Z/15/Z ). Publisher Copyright: © 2018 The Authors

PY - 2018/3/6

Y1 - 2018/3/6

N2 - 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. 

AB - 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. 

KW - cancer

KW - Cdc37 cochaperone

KW - client kinases

KW - disease-linked mutations

KW - fibroblast growth factor receptors

KW - Hsp90 chaperone

KW - protein folding

KW - structural and mechanistic insights

UR - https://www.scopus.com/pages/publications/85042333743

U2 - 10.1016/j.str.2018.01.016

DO - 10.1016/j.str.2018.01.016

M3 - Article

C2 - 29478821

AN - SCOPUS:85042333743

SN - 0969-2126

VL - 26

SP - 446-458.e8

JO - Structure

JF - Structure

IS - 3

ER -