Abstract
The major function of fibroblast growth factor2 (FGF2) is to induce the wound healing signaling and angiogenesis. Because FGF2 is a secretory protein without containing a signal peptide, it cannot pass cell membrane through the known ER/Golgi-dependent secretory pathway. An unconventional secretion mechanism of FGF2 has been reported. First, FGF2 must be recruited by Phosphatidylinositol 4,5-bisphosphate(PIP2) and phosphorylated by tyrosinekinase at Y73 . FGF2 forms a homo-oligomeric structure and then is inserted into membrane. The heparan sulfate proteoglycans in ECM pulls out the oligomeric FGF2. However, the molecular details of this unconventional secretion pathway is unknown, e.g. how does the FGF2 form oligomer? or what is the role of phosphorylation? We propose a high resolution FGF2-PIP2 complex structure that highly agrees with the NMR chemical shift data by molecular dynamics simulations. Furthermore, we found a stable dimeric structure “dimer31” from two identified FGF2 crystal packing forms. Based on this dimer31 structure, we find out that the major function of phosphorylated Y73 is to form an intermolecular salt bridge with R60 of the other subunit. Phosphorylated Y73 helps not only to form salt bridge directly but also promote R60 to find the Y73 in the other subunit. The results has helped us gain insights in unconventional secretion pathways.