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 stress conditions as a component of a multiprotein aggregate containing the p40 extravescicular domain of p65 synaptotagmin (Syt) 1 and S100A13. Since FGF1 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 interact in a cell-free system and the role of Cu2+ in this interaction. We report that FGF1, p40 Syt1, and S100A13 are able to bind Cu2+ with similar affinity and to interact in the presence of Cu2+ to form a multiprotein aggregate which is resistant to low concentrations of SDS and sensitive to reducing conditions and ultracentrifugation. The formation of this aggregate in the presence of Cu2+ is dependent on the presence of S100A13 and is mediated by cysteine-independent interactions between S100A13 and either FGF1 or p40 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 of S100A13 to export Cys-free FGF1 in response to stress. Lastly, tetrathiomolybdate, a Cu2+ chelator, significantly represses in a dose-dependent manner the heat shock-induced release of FGF1 and S100A13. These data suggest that S100A13 may be involved in the assembly of the multiprotein aggregate required for the release of FGF1 and that Cu2+ oxidation may be an essential post-translational intracellular modifier of this process.
Landriscina
M
M
Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, Maine 04074, USA.
Bagalá
C
C
Mandinova
A
A
Soldi
R
R
Micucci
I
I
Bellum
S
S
Prudovsky
I
I
Maciag
T
T
D000818:Animals; D002474:Cell-Free System; D003300:Copper / Q000494:pharmacology*; D003545:Cysteine / Q000378:metabolism; D003902:Detergents / Q000494:pharmacology; D019281:Dimerization; D016220:Fibroblast Growth Factor 1; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D006801:Humans; D008982:Molybdenum / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000378:metabolism; D011817:Rabbits; D009418:S100 Proteins / Q000378:metabolism*; D012967:Sodium Dodecyl Sulfate / Q000494:pharmacology; D013312:Stress, Physiological / Q000378:metabolism*; D050863:Synaptotagmin I
D003902:Detergents; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D009418:S100 Proteins; C511523:S100A13 protein, human; C494310:SYT1 protein, human; D050863:Synaptotagmin I; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; D012967:Sodium Dodecyl Sulfate; D003300:Copper; D008982:Molybdenum; C020809:tetrathiomolybdate; D003545:Cysteine