Role of Gold in Inflammation and Tristetraprolin Activity

The zinc finger protein tristetraprolin (TTP) regulates inflammation by downregulating cytokine mRNAs. Misregulation results in arthritis, sepsis and cancer, and there is an interest in modulating TTP activity with exogenous agents. Gold has anti-inflammatory properties and has recently been shown to modulate the signaling pathway that produces TTP, suggesting that TTP may be a target of gold. The reactivity of [Au-III(terpy)Cl]Cl-2 with TTP was investigated by UV/Vis spectroscopy, spin-filter inductively coupled plasma mass spectrometry, X-ray absorption spectroscopy and native electrospray ionization mass spectrometry. Au-III was found to replace zinc in the protein active site in the reduced Au-I form, with the Au-I ion coordinated to two cysteine residues in a linear geometry. The replacement of Zn-II with Au-I results in loss of both secondary structure and RNA binding function. In contrast, when (ZnTTP)-T-II is bound to its RNA target, no replacement of Zn-II with Au-I is observed, even in the presence of excess Au(III)terpy. This discovery of differential reactivity of gold with TTP versus TTP/RNA offers a potential strategy for selective targeting with gold complexes to control inflammation.