National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, 100101, Beijing, China.
College of Life Sciences, University of Chinese Academy of Sciences, 100049, Beijing, China.
Nat Commun. 2020 Jun 1;11(1):2702. doi: 10.1038/s41467-020-16523-y.
WIPI proteins (WIPI1-4) are mammalian PROPPIN family phosphoinositide effectors essential for autophagosome biogenesis. In addition to phosphoinositides, WIPI proteins can recognize a linear WIPI-interacting-region (WIR)-motif, but the underlying mechanism is poorly understood. Here, we determine the structure of WIPI3 in complex with the WIR-peptide from ATG2A. Unexpectedly, the WIR-peptide entwines around the WIPI3 seven-bladed β-propeller and binds to three sites in blades 1-3. The N-terminal part of the WIR-peptide forms a short strand that augments the periphery of blade 2, the middle segment anchors into an inter-blade hydrophobic pocket between blades 2-3, and the C-terminal aromatic tail wedges into another tailored pocket between blades 1-2. Mutations in three peptide-binding sites disrupt the interactions between WIPI3/4 and ATG2A and impair the ATG2A-mediated autophagic process. Thus, WIPI proteins recognize the WIR-motif by multi-sites in multi-blades and this multi-site-mediated peptide-recognition mechanism could be applicable to other PROPPIN proteins.
WIPI 蛋白（WIPI1-4）是哺乳动物 PROPPIN 家族的磷酸肌醇效应物，对自噬体的生物发生至关重要。除了磷酸肌醇外，WIPI 蛋白还可以识别线性 WIPI 相互作用区（WIR）基序，但潜在的机制尚不清楚。在这里，我们确定了 WIPI3 与来自 ATG2A 的 WIR 肽复合物的结构。出乎意料的是，WIR 肽缠绕在 WIPI3 的七叶β-螺旋桨周围，并与叶片 1-3 中的三个位点结合。WIR 肽的 N 端部分形成一个短链，增强了叶片 2 的外围，中间部分锚定在叶片 2-3 之间的叶片间疏水区，C 端芳香尾部楔入叶片 1-2 之间的另一个定制口袋。三个肽结合位点的突变破坏了 WIPI3/4 和 ATG2A 之间的相互作用，并损害了 ATG2A 介导的自噬过程。因此，WIPI 蛋白通过多叶片中的多个位点识别 WIR 基序，这种多位点介导的肽识别机制可能适用于其他 PROPPIN 蛋白。
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