Folding of Fibroblast Growth Factor 1 Is Critical for Its Nonclassical Release
by Prudovsky, I.; Kacer, D.; Davis, J.; Shah, V.; Jayanthi, S.; Huber, I.; Dakshinamurthy, R.; Ganter, O.; Soldi, R.; Neivandt, D.; Guvench, O.; Kumar, T. K. S.
Fibroblast growth factor 1 (FGF1), a ubiquitously expressed pro-angiogenic protein that is involved in tissue repair, carcinogenesis, and maintenance of vasculature stability, is released from the cells via a stress-dependent nonclassical secretory pathway. FGF1 secretion is a result of transmembrane translocation of this protein. It correlates with the ability of FGF1 to permeabilize membranes composed of acidic phospholipids. Like several other nonclassically exported proteins, FGF1 exhibits beta-barrel folding. To assess the role of folding of FGF1 in its secretion, we applied targeted mutagenesis in combination with a complex of biophysical methods and molecular dynamics studies, followed by artificial membrane permeabilization and stress-induced release experiments. It has been demonstrated that a mutation of proline 135 located in the C-terminus of FGF1 results in (i) partial unfolding of FGF1, (ii) a decrease in FGF1's ability to permeabilize bilayers composed of phosphatidylserine, and (iii) drastic inhibition of stress-induced FGF1 export. Thus, folding of FGF1 is critical for its nonclassical secretion.
- Journal
- Biochemistry
- Volume
- 55
- Issue
- 7
- Year
- 2016
- Start Page
- 1159-1167
- URL
- https://dx.doi.org/10.1021/acs.biochem.5b01341
- ISBN/ISSN
- 1520-4995; 0006-2960
- DOI
- 10.1021/acs.biochem.5b01341