Multi-site-mediated entwining of the linear WIR-motif around WIPI β-propellers for autophagy
Multi-site-mediated entwining of the linear WIR-motif around WIPI β-propellers for autophagy
复制标题
WIPI beta-螺旋桨周围线性 WIR 基序的多位点介导缠绕以实现自噬
DOI：
10.1038/s41467-020-16523-y
复制
发表时间：
2020-06-01
影响因子：
16.6
通讯作者：
Feng, Wei
中科院分区：
文献类型：
--
作者：
Ren, Jinqi;Liang, Ruobing;Feng, Wei
WIPI蛋白（WIPI 1 -4）是哺乳动物PROPPIN家族的磷酸肌醇效应物，对自噬体的生物合成至关重要。除了磷酸肌醇，WIPI蛋白可以识别线性WIPI相互作用区（WIR）基序，但其潜在机制知之甚少。在这里，我们确定了与来自ATG 2A的WIR肽复合的WIPI 3的结构。出乎意料的是，WIR肽缠绕在WIPI 3七叶片β螺旋桨周围，并结合到叶片1-3中的三个位点。WIR-肽的N-末端部分形成短链，其增强叶片2的周边，中间区段锚定到叶片2-3之间的叶片间疏水口袋中，并且C-末端芳香尾楔入叶片1-2之间的另一个定制口袋中。三个肽结合位点的突变破坏了WIPI 3/4和ATG 2A之间的相互作用，并损害了ATG 2A介导的自噬过程。因此，WIPI蛋白通过多叶片中的多位点识别WIR基序，并且这种多位点介导的肽识别机制可以适用于其他PROPPIN蛋白。
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 beta-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.