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Key steps in unconventional secretion of fibroblast growth factor 2 reconstituted with purified components

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    0478166 - ÚFCH JH 2018 RIV GB eng J - Journal Article
    Steringer, J. P. - Lange, S. - Čujová, Sabína - Šachl, Radek - Poojari, C. - Lolicato, F. - Beutel, O. - Müller, H.-M. - Unger, S. - Coskun, U. - Honigmann, A. - Vattulainen, I. - Hof, Martin - Freund, Ch. - Nickel, W.
    Key steps in unconventional secretion of fibroblast growth factor 2 reconstituted with purified components.
    eLife. Roč. 6, č. 2017 (2017), č. článku e28985. ISSN 2050-084X. E-ISSN 2050-084X
    R&D Projects: GA ČR(CZ) GC14-03141J
    Institutional support: RVO:61388955
    Keywords : Unconventional protein secretion * Fibroblast Growth Factor 2 * Protein translocation across membranes
    Subject RIV: CF - Physical ; Theoretical Chemistry
    OBOR OECD: Physical chemistry
    Impact factor: 7.616, year: 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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