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

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• 作者：Igor Prudovsky ; Doreen Kacer ; Julie Davis ; Varun Shah ; Srinivas Jayanthi ; Isabelle Huber ; Rajalingam Dakshinamurthy ; Owen Ganter ; Raffaella Soldi ; David Neivandt ; Olgun Guvench ; Thallapuranam Krishnaswamy Suresh Kumar
• 刊名：Biochemistry
• 出版年：2016
• 出版时间：February 23, 2016
• 年：2016
• 卷：55
• 期：7
• 页码：1159-1167
• 全文大小：482K
• ISSN：1520-4995

文摘

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.