An intrinsic quality-control mechanism ensures unconventional secretion of fibroblast growth factor 2 in a folded conformation.
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.
Torrado
Lucía Cespón
LC
Heidelberg University Biochemistry Center, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.
Temmerman
Koen
K
Müller
Hans-Michael
HM
Mayer
Matthias P
MP
Seelenmeyer
Claudia
C
Backhaus
Rafael
R
Nickel
Walter
W
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
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