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

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Maine Medical Center Research Institute

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Amino Acid Substitution, Animals, Calorimetry, Differential Scanning, Cell Membrane Permeability, Fibroblast Growth Factor 1, HEK293 Cells, Humans, Kinetics, Lipid Bilayers, Membranes, Artificial, Mice, Models, Molecular, Molecular Dynamics Simulation, Mutation, NIH 3T3 Cells, Permeability, Phosphatidylserines, Protein Conformation, Protein Folding, Recombinant Proteins


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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