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Isoform-specific inhibition of FGFR signaling achieved by a de-novo-designed mini-protein

Cellular signaling by fibroblast growth factor receptors (FGFRs) is a highly regulated process mediated by specific interactions between distinct subsets of fibroblast growth factor (FGF) ligands and two FGFR isoforms generated by alternative splicing: an epithelial b- and mesenchymal c-isoforms. He...

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Autores principales: Park, Joon Sung, Choi, Jungyuen, Cao, Longxing, Mohanty, Jyotidarsini, Suzuki, Yoshihisa, Park, Andy, Baker, David, Schlessinger, Joseph, Lee, Sangwon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9636537/
https://www.ncbi.nlm.nih.gov/pubmed/36288716
http://dx.doi.org/10.1016/j.celrep.2022.111545
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author Park, Joon Sung
Choi, Jungyuen
Cao, Longxing
Mohanty, Jyotidarsini
Suzuki, Yoshihisa
Park, Andy
Baker, David
Schlessinger, Joseph
Lee, Sangwon
author_facet Park, Joon Sung
Choi, Jungyuen
Cao, Longxing
Mohanty, Jyotidarsini
Suzuki, Yoshihisa
Park, Andy
Baker, David
Schlessinger, Joseph
Lee, Sangwon
author_sort Park, Joon Sung
collection PubMed
description Cellular signaling by fibroblast growth factor receptors (FGFRs) is a highly regulated process mediated by specific interactions between distinct subsets of fibroblast growth factor (FGF) ligands and two FGFR isoforms generated by alternative splicing: an epithelial b- and mesenchymal c-isoforms. Here, we investigate the properties of a mini-protein, mb7, developed by an in silico design strategy to bind to the ligand-binding region of FGFR2. We describe structural, biophysical, and cellular analyses demonstrating that mb7 binds with high affinity to the c-isoforms of FGFR, resulting in inhibition of cellular signaling induced by a subset of FGFs that preferentially activate c-isoforms of FGFR. Notably, as mb7 blocks interaction between FGFR with Klotho proteins, it functions as an antagonist of the metabolic hormones FGF19 and FGF21, providing mechanistic insights and strategies for the development of therapeutics for diseases driven by aberrantly activated FGFRs.
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spelling pubmed-96365372022-11-05 Isoform-specific inhibition of FGFR signaling achieved by a de-novo-designed mini-protein Park, Joon Sung Choi, Jungyuen Cao, Longxing Mohanty, Jyotidarsini Suzuki, Yoshihisa Park, Andy Baker, David Schlessinger, Joseph Lee, Sangwon Cell Rep Article Cellular signaling by fibroblast growth factor receptors (FGFRs) is a highly regulated process mediated by specific interactions between distinct subsets of fibroblast growth factor (FGF) ligands and two FGFR isoforms generated by alternative splicing: an epithelial b- and mesenchymal c-isoforms. Here, we investigate the properties of a mini-protein, mb7, developed by an in silico design strategy to bind to the ligand-binding region of FGFR2. We describe structural, biophysical, and cellular analyses demonstrating that mb7 binds with high affinity to the c-isoforms of FGFR, resulting in inhibition of cellular signaling induced by a subset of FGFs that preferentially activate c-isoforms of FGFR. Notably, as mb7 blocks interaction between FGFR with Klotho proteins, it functions as an antagonist of the metabolic hormones FGF19 and FGF21, providing mechanistic insights and strategies for the development of therapeutics for diseases driven by aberrantly activated FGFRs. 2022-10-25 /pmc/articles/PMC9636537/ /pubmed/36288716 http://dx.doi.org/10.1016/j.celrep.2022.111545 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ).
spellingShingle Article
Park, Joon Sung
Choi, Jungyuen
Cao, Longxing
Mohanty, Jyotidarsini
Suzuki, Yoshihisa
Park, Andy
Baker, David
Schlessinger, Joseph
Lee, Sangwon
Isoform-specific inhibition of FGFR signaling achieved by a de-novo-designed mini-protein
title Isoform-specific inhibition of FGFR signaling achieved by a de-novo-designed mini-protein
title_full Isoform-specific inhibition of FGFR signaling achieved by a de-novo-designed mini-protein
title_fullStr Isoform-specific inhibition of FGFR signaling achieved by a de-novo-designed mini-protein
title_full_unstemmed Isoform-specific inhibition of FGFR signaling achieved by a de-novo-designed mini-protein
title_short Isoform-specific inhibition of FGFR signaling achieved by a de-novo-designed mini-protein
title_sort isoform-specific inhibition of fgfr signaling achieved by a de-novo-designed mini-protein
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9636537/
https://www.ncbi.nlm.nih.gov/pubmed/36288716
http://dx.doi.org/10.1016/j.celrep.2022.111545
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