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

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. In order 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.

Authors:
 [1];  [2];  [3];  [3];  [3];  [3];  [3];  [4];  [2];  [5];  [6];  [3]
+ Show Author Affiliations
  1. Maine Medical Center Research Inst. (MMCRI), Scarborough, MA (United States); Univ. of Maine, Orono, MA (United States). Graduate School of Biomedical Science and Engineering
  2. Maine Medical Center Research Inst. (MMCRI), Scarborough, MA (United States)
  3. Univ. of Arkansas, Fayetteville, AR (United States). Dept. of Chemistry and Biochemistry
  4. Univ. of New England, Portland, MA (United States). College of Pharmacy
  5. Univ. of Maine, Orono, MA (United States). Graduate School of Biomedical Science and Engineering
  6. Univ. of Maine, Orono, MA (United States). Graduate School of Biomedical Science and Engineering; Univ. of New England, Portland, MA (United States). College of Pharmacy
Publication Date:
Research Org.:
Univ. of Arkansas, Fayetteville, AR (United States)
Sponsoring Org.:
USDOE Advanced Research Projects Agency - Energy (ARPA-E); National Institutes of Health (NIH); National Science Foundation (NSF)
OSTI Identifier:
1466969
Grant/Contract Number:  
FG02-01ER15161; P30 GM103392; TG-MCB120007; ACI-1053575
Resource Type:
Accepted Manuscript
Journal Name:
Biochemistry
Additional Journal Information:
Journal Volume: 55; Journal Issue: 7; Journal ID: ISSN 0006-2960
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Prudovsky, Igor, Kacer, Doreen, Davis, Julie, Shah, Varun, Jayanthi, Srinivas, Huber, Isabelle, Dakshinamurthy, Rajalingam, Ganter, Owen, Soldi, Raffaella, Neivandt, David, Guvench, Olgun, and Suresh Kumar, Thallapuranam Krishnaswamy. Folding of Fibroblast Growth Factor 1 Is Critical for Its Nonclassical Release. United States: N. p., 2016. Web. doi:10.1021/acs.biochem.5b01341.
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Prudovsky, Igor, Kacer, Doreen, Davis, Julie, Shah, Varun, Jayanthi, Srinivas, Huber, Isabelle, Dakshinamurthy, Rajalingam, Ganter, Owen, Soldi, Raffaella, Neivandt, David, Guvench, Olgun, & Suresh Kumar, Thallapuranam Krishnaswamy. Folding of Fibroblast Growth Factor 1 Is Critical for Its Nonclassical Release. United States. https://doi.org/10.1021/acs.biochem.5b01341
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Prudovsky, Igor, Kacer, Doreen, Davis, Julie, Shah, Varun, Jayanthi, Srinivas, Huber, Isabelle, Dakshinamurthy, Rajalingam, Ganter, Owen, Soldi, Raffaella, Neivandt, David, Guvench, Olgun, and Suresh Kumar, Thallapuranam Krishnaswamy. Tue . "Folding of Fibroblast Growth Factor 1 Is Critical for Its Nonclassical Release". United States. https://doi.org/10.1021/acs.biochem.5b01341. https://www.osti.gov/servlets/purl/1466969.
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@article{osti_1466969,
title = {Folding of Fibroblast Growth Factor 1 Is Critical for Its Nonclassical Release},
author = {Prudovsky, Igor and Kacer, Doreen and Davis, Julie and Shah, Varun and Jayanthi, Srinivas and Huber, Isabelle and Dakshinamurthy, Rajalingam and Ganter, Owen and Soldi, Raffaella and Neivandt, David and Guvench, Olgun and Suresh Kumar, Thallapuranam Krishnaswamy},
abstractNote = {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. In order 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.},
doi = {10.1021/acs.biochem.5b01341},
journal = {Biochemistry},
number = 7,
volume = 55,
place = {United States},
year = {Tue Feb 02 00:00:00 EST 2016},
month = {Tue Feb 02 00:00:00 EST 2016}
}
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