Multi-site-mediated entwining of the linear WIR-motif around WIPI β-propellers for autophagy

被引：32

作者：

Ren, Jinqi ^{[1
]}

Liang, Ruobing ^{[1
,2
]}

Wang, Wenjuan ^{[1
]}

Zhang, Dachuan ^{[3
]}

Yu, Li ^{[3
]}

Feng, Wei ^{[1
,2
]}

机构：

[1] Chinese Acad Sci, CAS Ctr Excellence Biomacromol, Inst Biophys, Natl Lab Biomacromol, 15 Datun Rd, Beijing 100101, Peoples R China

[2] Univ Chinese Acad Sci, Coll Life Sci, Beijing 100049, Peoples R China

[3] Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China

来源：

NATURE COMMUNICATIONS | 2020年 / 11卷 / 01期

基金：

国家重点研发计划; 中国国家自然科学基金;

关键词：

PHOSPHATIDYLINOSITOL; 3-PHOSPHATE; BINDING-SITES; MUTATIONS; PROPPINS; PROTEINS; DISTINCT; FAMILY; ATG21; PI3P;

D O I：

10.1038/s41467-020-16523-y

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：9