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Disease Variants of FGFR3 Reveal Molecular Basis for the Recognition and Additional Roles for Cdc37 in Hsp90 Chaperone System
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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846801/ https://www.ncbi.nlm.nih.gov/pubmed/29478821 http://dx.doi.org/10.1016/j.str.2018.01.016 |
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author | 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 |
author_facet | 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 |
author_sort | Bunney, Tom D. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5846801 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-58468012018-03-13 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. Breeze, Alexander L. Katan, Matilda Structure Article 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. Cell Press 2018-03-06 /pmc/articles/PMC5846801/ /pubmed/29478821 http://dx.doi.org/10.1016/j.str.2018.01.016 Text en © 2018 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article 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 Disease Variants of FGFR3 Reveal Molecular Basis for the Recognition and Additional Roles for Cdc37 in Hsp90 Chaperone System |
title | Disease Variants of FGFR3 Reveal Molecular Basis for the Recognition and Additional Roles for Cdc37 in Hsp90 Chaperone System |
title_full | Disease Variants of FGFR3 Reveal Molecular Basis for the Recognition and Additional Roles for Cdc37 in Hsp90 Chaperone System |
title_fullStr | Disease Variants of FGFR3 Reveal Molecular Basis for the Recognition and Additional Roles for Cdc37 in Hsp90 Chaperone System |
title_full_unstemmed | Disease Variants of FGFR3 Reveal Molecular Basis for the Recognition and Additional Roles for Cdc37 in Hsp90 Chaperone System |
title_short | Disease Variants of FGFR3 Reveal Molecular Basis for the Recognition and Additional Roles for Cdc37 in Hsp90 Chaperone System |
title_sort | disease variants of fgfr3 reveal molecular basis for the recognition and additional roles for cdc37 in hsp90 chaperone system |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846801/ https://www.ncbi.nlm.nih.gov/pubmed/29478821 http://dx.doi.org/10.1016/j.str.2018.01.016 |
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