Low Stability of Integrin-Binding Deficient Mutant of FGF1 Restricts Its Biological Activity
Fibroblast growth factor 1 (FGF1) has been shown to interact with integrin α<sub>v</sub>β<sub>3</sub> through a specific binding site, involving Arg35 residue. The FGF1 mutant (R35E) with impaired integrin binding was found to be defective in its proliferati...
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MDPI AG
2019-08-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/8/8/899 |
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| author | Anna Szlachcic Martyna Sochacka Aleksandra Czyrek Lukasz Opalinski Daniel Krowarsch Jacek Otlewski Malgorzata Zakrzewska |
| author_facet | Anna Szlachcic Martyna Sochacka Aleksandra Czyrek Lukasz Opalinski Daniel Krowarsch Jacek Otlewski Malgorzata Zakrzewska |
| author_sort | Anna Szlachcic |
| collection | DOAJ |
| description | Fibroblast growth factor 1 (FGF1) has been shown to interact with integrin α<sub>v</sub>β<sub>3</sub> through a specific binding site, involving Arg35 residue. The FGF1 mutant (R35E) with impaired integrin binding was found to be defective in its proliferative response, although it was still able to interact with FGF receptors (FGFR) and heparin and induce the activation of downstream signaling pathways. Here, we demonstrate that the lack of mitogenic potential of R35E mutant is directly caused by its decreased thermodynamic stability and susceptibility to proteolytic degradation. Introduction of three stabilizing mutations into R35E variant compensated the effect of destabilizing R35E mutation and restored the proliferation potential of FGF1. Moreover, the stabilized R35E variant regained both anti-apoptotic and wound healing activities, while remaining defective in binding to integrin α<sub>v</sub>β<sub>3</sub>. Our results suggest that the thermodynamic stability and resistance to degradation, rather than the interaction with integrin are required for mitogenic response of FGF1. |
| first_indexed | 2024-03-12T11:13:12Z |
| format | Article |
| id | doaj.art-0c367a45b8d1447bb3ca64eca4bdc6e9 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T11:13:12Z |
| publishDate | 2019-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-0c367a45b8d1447bb3ca64eca4bdc6e92023-09-02T02:24:08ZengMDPI AGCells2073-44092019-08-018889910.3390/cells8080899cells8080899Low Stability of Integrin-Binding Deficient Mutant of FGF1 Restricts Its Biological ActivityAnna Szlachcic0Martyna Sochacka1Aleksandra Czyrek2Lukasz Opalinski3Daniel Krowarsch4Jacek Otlewski5Malgorzata Zakrzewska6Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, 50-383 Wroclaw, PolandDepartment of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, 50-383 Wroclaw, PolandDepartment of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, 50-383 Wroclaw, PolandDepartment of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, 50-383 Wroclaw, PolandDepartment of Protein Biotechnology, Faculty of Biotechnology, University of Wroclaw, 50-383 Wroclaw, PolandDepartment of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, 50-383 Wroclaw, PolandDepartment of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, 50-383 Wroclaw, PolandFibroblast growth factor 1 (FGF1) has been shown to interact with integrin α<sub>v</sub>β<sub>3</sub> through a specific binding site, involving Arg35 residue. The FGF1 mutant (R35E) with impaired integrin binding was found to be defective in its proliferative response, although it was still able to interact with FGF receptors (FGFR) and heparin and induce the activation of downstream signaling pathways. Here, we demonstrate that the lack of mitogenic potential of R35E mutant is directly caused by its decreased thermodynamic stability and susceptibility to proteolytic degradation. Introduction of three stabilizing mutations into R35E variant compensated the effect of destabilizing R35E mutation and restored the proliferation potential of FGF1. Moreover, the stabilized R35E variant regained both anti-apoptotic and wound healing activities, while remaining defective in binding to integrin α<sub>v</sub>β<sub>3</sub>. Our results suggest that the thermodynamic stability and resistance to degradation, rather than the interaction with integrin are required for mitogenic response of FGF1.https://www.mdpi.com/2073-4409/8/8/899fibroblast growth factor 1integrin α<sub>v</sub>β<sub>3</sub>protein stabilityproteolytic degradationmitogenic activityprotein-protein interactionanti-apoptotic activity |
| spellingShingle | Anna Szlachcic Martyna Sochacka Aleksandra Czyrek Lukasz Opalinski Daniel Krowarsch Jacek Otlewski Malgorzata Zakrzewska Low Stability of Integrin-Binding Deficient Mutant of FGF1 Restricts Its Biological Activity Cells fibroblast growth factor 1 integrin α<sub>v</sub>β<sub>3</sub> protein stability proteolytic degradation mitogenic activity protein-protein interaction anti-apoptotic activity |
| title | Low Stability of Integrin-Binding Deficient Mutant of FGF1 Restricts Its Biological Activity |
| title_full | Low Stability of Integrin-Binding Deficient Mutant of FGF1 Restricts Its Biological Activity |
| title_fullStr | Low Stability of Integrin-Binding Deficient Mutant of FGF1 Restricts Its Biological Activity |
| title_full_unstemmed | Low Stability of Integrin-Binding Deficient Mutant of FGF1 Restricts Its Biological Activity |
| title_short | Low Stability of Integrin-Binding Deficient Mutant of FGF1 Restricts Its Biological Activity |
| title_sort | low stability of integrin binding deficient mutant of fgf1 restricts its biological activity |
| topic | fibroblast growth factor 1 integrin α<sub>v</sub>β<sub>3</sub> protein stability proteolytic degradation mitogenic activity protein-protein interaction anti-apoptotic activity |
| url | https://www.mdpi.com/2073-4409/8/8/899 |
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