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. 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.affiliation: Maine Medical Center Research Institute , 81 Research Drive, Scarborough, Maine 04074, United States.|Graduate School of Biomedical Science and Engineering, University of Maine , Jenness Hall, Orono, Maine 04469, United States.
authors.forename: Igor
authors.initials: I
authors.lastname: Prudovsky
authors.affiliation: Maine Medical Center Research Institute , 81 Research Drive, Scarborough, Maine 04074, United States.
authors.forename: Doreen
authors.initials: D
authors.lastname: Kacer
authors.affiliation: Department of Chemistry and Biochemistry, University of Arkansas , Chemistry Building, Fayetteville, Arkansas 72701, United States.
authors.forename: Julie
authors.initials: J
authors.lastname: Davis
authors.affiliation: Department of Chemistry and Biochemistry, University of Arkansas , Chemistry Building, Fayetteville, Arkansas 72701, United States.
authors.forename: Varun
authors.initials: V
authors.lastname: Shah
authors.affiliation: Department of Chemistry and Biochemistry, University of Arkansas , Chemistry Building, Fayetteville, Arkansas 72701, United States.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Jayanthi
authors.affiliation: Department of Chemistry and Biochemistry, University of Arkansas , Chemistry Building, Fayetteville, Arkansas 72701, United States.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Huber
authors.affiliation: Department of Chemistry and Biochemistry, University of Arkansas , Chemistry Building, Fayetteville, Arkansas 72701, United States.
authors.forename: Rajalingam
authors.initials: R
authors.lastname: Dakshinamurthy
authors.affiliation: College of Pharmacy, University of New England , Pharmacy Building, 716 Stevens Avenue, Portland, Maine 04103, United States.
authors.forename: Owen
authors.initials: O
authors.lastname: Ganter
authors.affiliation: Maine Medical Center Research Institute , 81 Research Drive, Scarborough, Maine 04074, United States.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Soldi
authors.affiliation: Graduate School of Biomedical Science and Engineering, University of Maine , Jenness Hall, Orono, Maine 04469, United States.
authors.forename: David
authors.initials: D
authors.lastname: Neivandt
authors.affiliation: Graduate School of Biomedical Science and Engineering, University of Maine , Jenness Hall, Orono, Maine 04469, United States.|College of Pharmacy, University of New England , Pharmacy Building, 716 Stevens Avenue, Portland, Maine 04103, United States.
authors.forename: Olgun
authors.initials: O
authors.lastname: Guvench
authors.affiliation: Department of Chemistry and Biochemistry, University of Arkansas , Chemistry Building, Fayetteville, Arkansas 72701, United States.
authors.forename: Thallapuranam Krishnaswamy
authors.initials: TK
authors.lastname: Suresh Kumar
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002152:Calorimetry, Differential Scanning; D002463:Cell Membrane Permeability; D016220:Fibroblast Growth Factor 1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008051:Lipid Bilayers / Q000737:chemistry; D008567:Membranes, Artificial; D051379:Mice; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009154:Mutation; D041681:NIH 3T3 Cells; D010539:Permeability; D010718:Phosphatidylserines / Q000737:chemistry; D011487:Protein Conformation; D017510:Protein Folding; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D008051:Lipid Bilayers; D008567:Membranes, Artificial; D010718:Phosphatidylserines; D011994:Recombinant Proteins; D016220:Fibroblast Growth Factor 1
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