title: An intrinsic quality-control mechanism ensures unconventional secretion of fibroblast growth factor 2 in a folded conformation.
abstract: Fibroblast growth factor 2 (FGF2) is a proangiogenic mitogen that is secreted by an unconventional mechanism, which does not depend on a functional ER-Golgi system. FGF2 is first recruited to the inner leaflet of plasma membranes, in a process that is mediated by the phosphoinositide PtdIns(4,5)P(2). On the extracellular side, membrane-proximal FGF2-binding sites provided by heparan-sulfate proteoglycans are essential for trapping and accumulating FGF2 in the extracellular space. Here we demonstrate that FGF2 membrane translocation can occur in a folded conformation, i.e. unfolded molecules are not obligatory intermediates in FGF2 secretion. Furthermore, we find that initial sorting into its export pathway requires FGF2 to be folded, because the interaction with PtdIns(4,5)P(2) is lost upon unfolding of FGF2. Our combined findings suggest an intrinsic quality-control mechanism that ensures extracellular accumulation of FGF2 in a biologically active form.
authors.affiliation: Heidelberg University Biochemistry Center, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.
authors.forename: Lucía Cespón
authors.initials: LC
authors.lastname: Torrado
authors.forename: Koen
authors.initials: K
authors.lastname: Temmerman
authors.forename: Hans-Michael
authors.initials: HM
authors.lastname: Müller
authors.forename: Matthias P
authors.initials: MP
authors.lastname: Mayer
authors.forename: Claudia
authors.initials: C
authors.lastname: Seelenmeyer
authors.forename: Rafael
authors.initials: R
authors.lastname: Backhaus
authors.forename: Walter
authors.initials: W
authors.lastname: Nickel
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D016222:Fibroblast Growth Factor 2 / Q000737:chemistry* / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007074:Immunoglobulin G / Q000737:chemistry / Q000378:metabolism; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D011485:Protein Binding; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D007074:Immunoglobulin G; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D011993:Recombinant Fusion Proteins; D016222:Fibroblast Growth Factor 2; D049452:Green Fluorescent Proteins