Journal
BIOCHEMISTRY
Volume 55, Issue 7, Pages 1159-1167Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.biochem.5b01341
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Funding
- Maine Medical Center
- Maine Cancer Foundation
- National Institutes of Health (NIH) [RO1 HL35627]
- NIH (NCRR COBRE Grant) [1 P20 RR15569, P30 GM103450, R01 CA172631]
- U.S. Department of Energy [DE-FG02-01ER15161]
- National Science Foundation
- Arkansas Biosciences Institute
- National Science Foundation [MCB-1453529]
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [1453529] Funding Source: National Science Foundation
- U.S. Department of Energy (DOE) [DE-FG02-01ER15161] Funding Source: U.S. Department of Energy (DOE)
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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.
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