Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Mol Cell. 2012 Aug 10;47(3):339-48. doi: 10.1016/j.molcel.2012.05.027. Epub 2012 Jun 14.
Macroautophagy is essential to cell survival during starvation and proceeds by the growth of a double-membraned phagophore, which engulfs cytosol and other substrates. The synthesis and recognition of the lipid phosphatidylinositol 3-phosphate, PI(3)P, is essential for autophagy. The key autophagic PI(3)P sensors, which are conserved from yeast to humans, belong to the PROPPIN family. Here we report the crystal structure of the yeast PROPPIN Hsv2. The structure consists of a seven-bladed β-propeller and, unexpectedly, contains two pseudo-equivalent PI(3)P binding sites on blades 5 and 6. These two sites both contribute to membrane binding in vitro and are collectively required for full autophagic function in yeast. These sites function in concert with membrane binding by a hydrophobic loop in blade 6, explaining the specificity of the PROPPINs for membrane-bound PI(3)P. These observations thus provide a structural and mechanistic framework for one of the conserved central molecular recognition events in autophagy.
自噬对于饥饿状态下的细胞存活至关重要，其过程是通过双层吞噬体的生长来实现的，该吞噬体吞噬细胞质和其他底物。脂质磷脂酰肌醇 3-磷酸（PI(3)P）的合成和识别对于自噬是必不可少的。自噬的关键 PI(3)P 传感器在从酵母到人中都得到了保守，属于 PROPPIN 家族。在这里，我们报告了酵母 PROPPIN Hsv2 的晶体结构。该结构由一个七叶β-螺旋桨组成，出人意料的是，在第 5 和第 6 叶上包含两个伪等价的 PI(3)P 结合位点。这两个位点都有助于体外的膜结合，并且在酵母中完全自噬功能中都是必需的。这些位点与叶片 6 中的疏水环的膜结合协同作用，解释了 PROPPIN 对膜结合 PI(3)P 的特异性。这些观察结果为自噬中保守的核心分子识别事件之一提供了结构和机制框架。
