Key steps in unconventional secretion of fibroblast growth factor 2 reconstituted with purified components
- Heidelberg University, Germany
- Freie Universität Berlin, Germany
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Germany
- Academy of Sciences of the Czech Republic, Czech Republic
- University of Helsinki, Finland
- Max Planck Institute of Molecular Cell Biology and Genetics, Germany
- Paul Langerhans Institute Dresden, Germany
Abstract
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.
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Funding
Deutsche Forschungsgemeinschaft (SFB/TRR 83 SFB/TRR 186 SFB 854 SFB 958 DFG Ni 423/6-1)
- Ünal Coskun
- Martin Hof
- Christian Freund
Czech Science Foundation (14-03141)
- Martin Hof
European Research Council (Advanced Grant 290974 CROWDED-PRO-LIPIDS)
- Ilpo Vattulainen
Academy of Finland (Center of Excellence projects 272130 and 307415)
- Ilpo Vattulainen
Sigrid Juselius Foundation
- Ilpo Vattulainen
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2017, Steringer et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Key steps in unconventional secretion of fibroblast growth factor 2 reconstituted with purified components
eLife 6:e28985.
https://doi.org/10.7554/eLife.28985
