Folding of Fibroblast Growth Factor 1 Is Critical for Its Nonclassical Release

Biochemistry
Igor PrudovskyThallapuranam Krishnaswamy Suresh Kumar

Abstract

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 β-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.

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Citations

May 10, 2020·Nature Communications·ShengPeng WangStefan Offermanns
Jun 2, 2020·Cytokine & Growth Factor Reviews·Katarzyna Dominika SluzalskaMalgorzata Zakrzewska
Nov 24, 2020·The Cell Surface·Michael J CohenPeter N Lipke
Jul 23, 2018·Archives of Biochemistry and Biophysics·Julie Eberle DavisThallapuranam Krishnaswamy Suresh Kumar

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