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Key steps in unconventional secretion of fibroblast growth factor 2 reconstituted with purified components.
eLife 6:e28985 (2017)
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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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Fibroblast Growth Factor 2 ; Unconventional Protein Secretion ; Biochemistry ; Biophysics ; Human ; Oligomerization ; Phosphoinositide ; Protein Translocation Across Membranes ; Reconstitution With Purified Components ; Structural Biology
ISSN (print) / ISBN
2050-084X
e-ISSN
2050-084X
Journal
eLife
Quellenangaben
Volume: 6,
Article Number: e28985
Publisher
eLife Sciences Publications
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Pancreatic Islet Research (IPI)