Patwari Parth, Higgins Luke J, Chutkow William A, Yoshioka Jun, Lee Richard T
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Cambridge, Massachusetts 02139.
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Cambridge, Massachusetts 02139.
J Biol Chem. 2006 Aug 4;281(31):21884-21891. doi: 10.1074/jbc.M600427200. Epub 2006 Jun 9.
The thioredoxin system plays an important role in maintaining a reducing environment in the cell. Recently, several thioredoxin binding partners have been identified and proposed to mediate aspects of redox signaling, but the significance of these interactions is unclear in part due to incomplete understanding of the mechanism for thioredoxin binding. Thioredoxin-interacting protein (Txnip) is critical for regulation of glucose metabolism, the only currently known function of which is to bind and inhibit thioredoxin. We explored the mechanism of the Txnip-thioredoxin interaction and present evidence that Txnip and thioredoxin form a stable disulfide-linked complex. We identified two Txnip cysteines that are important for thioredoxin binding and showed that this interaction is consistent with a disulfide exchange reaction between oxidized Txnip and reduced thioredoxin. These cysteines are not conserved in the broader family of arrestin domain-containing proteins, and we demonstrate that the thioredoxin-binding property of Txnip is unique. These data suggest that Txnip is a target of reduced thioredoxin and provide insight into the potential role of Txnip as a redox-sensitive signaling protein.
硫氧还蛋白系统在维持细胞内的还原环境中起着重要作用。最近，已鉴定出几种硫氧还蛋白结合伴侣，并提出它们可介导氧化还原信号传导的各个方面，但这些相互作用的重要性尚不清楚，部分原因是对硫氧还蛋白结合机制的理解不完整。硫氧还蛋白相互作用蛋白（Txnip）对葡萄糖代谢的调节至关重要，其目前已知的唯一功能是结合并抑制硫氧还蛋白。我们探索了Txnip与硫氧还蛋白相互作用的机制，并提供证据表明Txnip和硫氧还蛋白形成了稳定的二硫键连接复合物。我们鉴定出两个对硫氧还蛋白结合很重要的Txnip半胱氨酸，并表明这种相互作用与氧化型Txnip和还原型硫氧还蛋白之间的二硫键交换反应一致。这些半胱氨酸在含抑制蛋白结构域的更广泛蛋白质家族中并不保守，并且我们证明Txnip的硫氧还蛋白结合特性是独特的。这些数据表明Txnip是还原型硫氧还蛋白的靶标，并为Txnip作为氧化还原敏感信号蛋白的潜在作用提供了见解。
