Key steps in unconventional secretion of fibroblast growth factor 2 reconstituted with purified components.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 28722655.
- Also identified by DOI 10.7554/eLife.28985 and PMC identifier 5601999.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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)P<sub>2</sub>-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)P<sub>2</sub> and heparan sulfates on opposing sides of the membrane. Based on atomistic molecular dynamics simulations, we propose a mechanism that drives PI(4,5)P<sub>2</sub> 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.
Medical subject headings
- Fibroblast Growth Factor 2
- Membrane Transport Proteins
- Protein Multimerization
- Secretory Vesicles