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

作者：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; Breeze Alexander L^*; Katan Matilda^*

来源：Structure, 2018, 26(3): 446-+.

DOI：10.1016/j.str.2018.01.016

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 diseaselinked 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.

• 出版日期2018-3-6