Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205, USA.
Protein Sci. 2011 Jan;20(1):131-9. doi: 10.1002/pro.544.
Lysine propionylation is a recently identified post-translational modification that has been observed in proteins such as p53 and histones and is thought to play a role similar to acetylation in modulating protein activity. Members of the sirtuin family of deacetylases have been shown to have depropionylation activity, although the way in which the sirtuin catalytic site accommodates the bulkier propionyl group is not clear. We have determined the 1.8 Å structure of a Thermotoga maritima sirtuin, Sir2Tm, bound to a propionylated peptide derived from p53. A comparison with the structure of Sir2Tm bound to an acetylated peptide shows that hydrophobic residues in the active site shift to accommodate the bulkier propionyl group. Isothermal titration calorimetry data show that Sir2Tm binds propionylated substrates more tightly than acetylated substrates, but kinetic assays reveal that the catalytic rate of Sir2Tm deacylation of propionyl-lysine is slightly reduced to acetyl-lysine. These results serve to broaden our understanding of the newly identified propionyl-lysine modification and the ability of sirtuins to depropionylate, as well as deacetylate, substrates.
赖氨酸丙酰化是一种最近发现的翻译后修饰，已在 p53 和组蛋白等蛋白质中观察到，被认为在调节蛋白质活性方面发挥类似于乙酰化的作用。去乙酰化酶家族的 sirtuin 成员已被证明具有脱丙酰化活性，尽管 sirtuin 催化位点适应较大的丙酰基的方式尚不清楚。我们已经确定了与源自 p53 的丙酰化肽结合的 Thermotoga maritima sirtuin（Sir2Tm）的 1.8 Å 结构。与与乙酰化肽结合的 Sir2Tm 结构的比较表明，活性位点中的疏水性残基发生移位以适应较大的丙酰基。等温热滴定法数据表明，Sir2Tm 与丙酰化底物的结合比乙酰化底物更紧密，但动力学测定显示 Sir2Tm 脱酰化丙酰化赖氨酸的催化速率略低于乙酰化赖氨酸。这些结果有助于拓宽我们对新发现的丙酰化赖氨酸修饰以及 sirtuins 去丙酰化和去乙酰化底物的能力的理解。
