Kessler Roman, Hausmann George, Basler Konrad
Institut für Molekularbiologie, Universität Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
Mech Dev. 2009 Aug-Sep;126(8-9):752-9. doi: 10.1016/j.mod.2009.04.003. Epub 2009 Jun 2.
In Drosophila Pygopus (Pygo) and Legless (Lgs)/BCL9 are integral components of the nuclear Wnt/Wg signaling machine. Despite intense research, ideas that account for their mode of action remain speculative. One proposition, based on a recently discovered function of PHD fingers, is that Pygo, through its PHD, may decipher the histone code. We found that human, but not Drosophila, Pygo robustly interacts with a histone-H3 peptide methylated at lysine-4. The different binding behavior is due to a single amino acid change that appears unique to Drosophilidae Pygo proteins. Rescue experiments with predicted histone binding mutants showed that in Drosophila the ability to bind histones is not essential. Further experiments with Pygo-Lgs fusions instead demonstrated that the crucial role of the PHD is to provide an interaction motif to bind Lgs. Our results reveal an interesting evolutionary dichotomy in Pygo structure-function, as well as evidence underpinning the chain of adaptors model.
在果蝇中,矮胖蛋白(Pygo)和无腿蛋白(Lgs)/BCL9是核内Wnt/Wg信号传导机制的重要组成部分。尽管进行了深入研究,但关于它们作用方式的观点仍属推测。基于最近发现的PHD指结构域的功能,一种观点认为,Pygo可能通过其PHD结构域来解读组蛋白密码。我们发现,人类的Pygo能与赖氨酸-4甲基化的组蛋白H3肽强烈相互作用,而果蝇的Pygo则不能。这种不同的结合行为是由一个氨基酸变化导致的,该变化似乎是果蝇科Pygo蛋白所特有的。对预测的组蛋白结合突变体进行的拯救实验表明,在果蝇中,结合组蛋白的能力并非必需。相反,用Pygo-Lgs融合蛋白进行的进一步实验表明,PHD的关键作用是提供一个与Lgs结合的相互作用基序。我们的结果揭示了Pygo结构与功能中有趣的进化二分法,以及支持衔接蛋白模型链条的证据。