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First published online 25 August 2009
doi: 10.1242/jcs.049791

Journal of Cell Science 122, 3322-3329 (2009)
Published by The Company of Biologists 2009
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Research Article

An intrinsic quality-control mechanism ensures unconventional secretion of fibroblast growth factor 2 in a folded conformation

Lucía Cespón Torrado1, Koen Temmerman1, Hans-Michael Müller1, Matthias P. Mayer2, Claudia Seelenmeyer1, Rafael Backhaus1 and Walter Nickel1,*

1 Heidelberg University Biochemistry Center, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany
2 Zentrum für Molekulare Biologie der Universität Heidelberg, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany

* Author for correspondence (walter.nickel{at}bzh.uni-heidelberg.de)

Accepted 24 June 2009

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)P2. 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)P2 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.

Key words: Unconventional protein secretion, Non-classical export, Membrane translocation, Fibroblast growth factor 2, FGF2, Protein folding, Quality control


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