FGF2 is secreted from cells by an unconventional secretory pathway. This process is mediated by direct translocation across the plasma membrane. Here, we define the minimal molecular machinery required for FGF2 membrane translocation in a fully reconstituted inside-out vesicle system. FGF2 membrane translocation is thermodynamically driven by PI(4,5)P2-induced membrane insertion of FGF2 oligomers. The latter serve as dynamic translocation intermediates of FGF2 with a subunit number in the range of 8-12 FGF2 molecules. Vectorial translocation of FGF2 across the membrane is governed by sequential and mutually exclusive interactions with PI(4,5)P2 and heparan sulfates on opposing sides of the membrane. Based on atomistic molecular dynamics simulations, we propose a mechanism that drives PI(4,5)P2 dependent oligomerization of FGF2. Our combined findings establish a novel type of self-sustained protein translocation across membranes revealing the molecular basis of the unconventional secretory pathway of FGF2.

Department of Physics University of Helsinki Helsinki Finland Department of Physics Tampere University of Technology Tampere Finland

Department of Physics University of Helsinki Helsinki Finland Department of Physics Tampere University of Technology Tampere Finland MEMPHYS Center for Biomembrane Physics University of Southern Denmark Denmark United Kingdom

Heidelberg University Biochemistry Center Heidelberg Germany

Institut für Chemie und Biochemie Freie Universität Berlin Berlin Germany

J Heyrovský Institute of Physical Chemistry Academy of Sciences of the Czech Republic Prague Czech Republic

Max Planck Institute of Molecular Cell Biology and Genetics Dresden Germany

Paul Langerhans Institute Dresden Helmholtz Zentrum München University Hospital and Faculty of Medicine Carl Gustav Carus Technische Universität Dresden Dresden Germany Deutsches Zentrum fur Diabetesforschung Neuherberg Germany

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