National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China.
J Mol Biol. 2019 Mar 29;431(7):1494-1505. doi: 10.1016/j.jmb.2019.02.019. Epub 2019 Feb 22.
WIPI proteins are mammalian PROPPIN family members that bind to phosphoinositides and play prominent roles in autophagosome biogenesis. Two phosphoinositide-binding sites were previously described in yeast PROPPIN Hsv2 but remain to be determined in mammalian WIPI proteins. Here, we characterized four human WIPI proteins (WIPI1-4) and solved the structure of WIPI3. WIPI proteins can bind to PI(3)P and PI(3,5)P and adopt a conventional seven-bladed β-propeller fold. The structure of WIPI3 revealed that WIPI proteins also contain two sites embedded in blades 5 and 6 for recognizing phosphoinositides, resembling that in Hsv2. Structural comparison further demonstrated that the two conserved phosphoinositide-binding sites in PROPPIN proteins are not identical but intrinsically tend to recognize different types of phosphoinositides. This work provides the structural evidence to support the conservation of the two phosphoinositide-binding sites in WIPI proteins and also uncovers the potential phosphoinositide-binding selectivity for each site.
WIPI 蛋白是哺乳动物 PROPPIN 家族的成员，它们与磷酸肌醇结合，并在自噬体生物发生中发挥重要作用。先前在酵母 PROPPIN Hsv2 中描述了两个磷酸肌醇结合位点，但在哺乳动物 WIPI 蛋白中仍有待确定。在这里，我们对四种人类 WIPI 蛋白（WIPI1-4）进行了表征，并解析了 WIPI3 的结构。WIPI 蛋白可以与 PI(3)P 和 PI(3,5)P 结合，并采用传统的七叶β-螺旋桨折叠。WIPI3 的结构揭示了 WIPI 蛋白还包含两个位于叶片 5 和 6 中的位点，用于识别磷酸肌醇，类似于 Hsv2 中的情况。结构比较进一步表明，PROPPIN 蛋白中的两个保守的磷酸肌醇结合位点并不相同，但本质上倾向于识别不同类型的磷酸肌醇。这项工作提供了结构证据，支持 WIPI 蛋白中两个磷酸肌醇结合位点的保守性，同时也揭示了每个位点潜在的磷酸肌醇结合选择性。
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