Copper induces the assembly of a multiprotein aggregate implicated in the release of fibroblast growth factor 1 in response to stress

Fibroblast growth factor (FGF) 1 is known to be released in response to str ess conditions as a component of a multiprotein aggregate containing the p4 0 extravescicular domain of p65 synaptotagmin (Syt) 1 and S100A13, Since FG F1 is a Cu2+-binding protein and Cu2+ is known to induce its dimerization, we evaluated the capacity of recombinant FGF1, p40 Syt1, and S100A13 to int eract in a cell-free system and the role of Cu2+ in this interaction. We re port that FGF1, p40 Syt1, and S100A13 are able to bind Cu2+ With Similar af finity and to interact in the presence of Cu2+ to form a multiprotein aggre gate which is resistant to low concentrations of SDS and sensitive to reduc ing conditions and ultracentrifugation, The formation of this aggregate in the presence of Cu2+ is dependent on the presence of S100A13 and is mediate d by cysteine-independent interactions between S100A13 and either FGF1 or p 40 Syt1, Interestingly, S100A13 is also able to interact in the presence of Cu2+ with Cys-free FGF1 and this observation may account for the ability o f S100A13 to export Cys-free FGF1 in response to stress. Lastly, tetrathiom olybdate, a Cu2+ chelator, significantly represses in a dose-dependent mann er the heat shock-induced release of FGF1 and S100A13, These data suggest t hat S100A13 may be involved in the assembly of the multiprotein aggregate r equired for the release of FGF1 and that Cu2+ oxidation may be an essential post-translational intracellular modifier of this process.