Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
Cells. 2021 May 14;10(5):1205. doi: 10.3390/cells10051205.
The genetic code that dictates how nucleic acids are translated into proteins is well known, however, the code through which proteins recognize membranes remains mysterious. In eukaryotes, this code is mediated by hundreds of membrane readers that recognize unique phosphatidylinositol phosphates (PIPs), which demark organelles to initiate localized trafficking and signaling events. The only superfamily which specifically detects all seven PIPs are the Phox homology (PX) domains. Here, we reveal that throughout evolution, these readers are universally regulated by the phosphorylation of their PIP binding surfaces based on our analysis of existing and modelled protein structures and phosphoproteomic databases. These PIP-stops control the selective targeting of proteins to organelles and are shown to be key determinants of high-fidelity PIP recognition. The protein kinases responsible include prominent cancer targets, underscoring the critical role of regulated membrane readership.
众所周知，决定核酸如何翻译成蛋白质的遗传密码是明确的，然而，蛋白质识别膜的密码仍然是神秘的。在真核生物中，这种密码是由数百种膜阅读器介导的，这些阅读器识别独特的磷脂酰肌醇磷酸（PIP），从而标记细胞器以启动局部运输和信号事件。唯一能够特异性检测所有七种 PIP 的超家族是 Phox 同源（PX）结构域。在这里，我们通过分析现有和建模的蛋白质结构和磷酸蛋白质组学数据库揭示，在整个进化过程中，这些阅读器普遍受到其 PIP 结合表面磷酸化的调节，基于我们的分析。这些 PIP 停止控制蛋白质对细胞器的选择性靶向，并且被证明是高保真 PIP 识别的关键决定因素。负责的蛋白激酶包括突出的癌症靶点，强调了受调控的膜阅读的关键作用。
