Fibroblast growth factor 2 (FGF2) is a key signaling molecule in
angiogenesis and inflammation. It is secreted by an unconventional
secretory mechanism involving phosphoinositide-dependent insertion of
FGF2 oligomers into the plasma membrane which is regulated by tyrosine
phosphorylation. We have shown that membrane insertion of FGF2
oligomers causes the formation of lipidic membrane pores with a toroidal
architecture that have been interpreted as translocation intermediates
during secretion of FGF2. We have found that two surface cysteines
uniquely present in FGF2 compared to signal-peptide-containing FGF
family members form disulfide bridges required for oligomerization, pore
formation and secretion of FGF2. The goals of this project are i.) to
determine the exact arrangement of disulfide bridges to reveal the
architecture of pore-forming FGF2 oligomers, ii.) to analyze the oligomeric
structure of secreted FGF2 on cell surfaces and iii.) to analyze a role of
auxiliary factors such as the cytoplasmic sulfhydryl oxidase ALR2 and
integral membrane proteins of the NOX family. Furthermore, based on
striking structural similarities between FGF2 and interleukin 1β (IL1β), we
will systematically address potential similarities in the unconventional
secretory mechanisms to challenge the hypothesis of a single molecular mechanism underlying unconventional secretion of of FGF2 and IL1β. The
results are expected to pave the way for the development of new lead
compounds of drugs with a high potential in the therapy of
autoinflammatory syndromes.