Potent and specific Atg8-targeting autophagy inhibitory peptides from giant ankyrins

被引：59

作者：

Li, Jianchao ^{[1
]}

Zhu, Ruichi ^{[1
]}

Chen, Keyu ^{[1
]}

Zheng, Hui ^{[2
,3
]}

Zhao, Hongyu ^{[2
,3
]}

Yuan, Chongzhen ^{[2
,3
]}

Zhang, Hong ^{[2
,3
]}

Wang, Chao ^{[1
,4
]}

Zhang, Mingjie ^{[1
,5
]}

机构：

[1] Hong Kong Univ Sci & Technol, State Key Lab Mol Neurosci, Div Life Sci, Kowloon, Hong Kong, Peoples R China

[2] Chinese Acad Sci, Inst Biophys, CAS Ctr Excellence Biomacromol, Natl Lab Biomacromol, Beijing, Peoples R China

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

[4] Univ Sci & Technol China, Sch Life Sci, Hefei Natl Lab Phys Sci Microscale, Hefei, Anhui, Peoples R China

[5] Hong Kong Univ Sci & Technol, Ctr Syst Biol & Human Hlth, Inst Adv Study, Kowloon, Hong Kong, Peoples R China

来源：

NATURE CHEMICAL BIOLOGY | 2018年 / 14卷 / 08期

基金：

中国国家自然科学基金;

关键词：

MONITORING AUTOPHAGY; MAMMALIAN AUTOPHAGY; 440-KD ANKYRIN(B); STRUCTURAL BASIS; INITIAL SEGMENT; LIR MOTIF; LC3; ATG8; BINDING; LOCALIZATION;

D O I：

10.1038/s41589-018-0082-8

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The mammalian Atg8 family proteins are central drivers of autophagy and contain six members, classified into the LC3 and GABARAP subfamilies. Due to their high sequence similarity and consequent functional overlaps, it is difficult to delineate specific functions of Atg8 proteins in autophagy. Here we discover a super-strong GABARAP-selective inhibitory peptide harbored in 270/480 kDa ankyrin-G and a super-potent pan-Atg8 inhibitory peptide from 440 kDa ankyrin-B. Structural studies elucidate the mechanism governing the Atg8 binding potency and selectivity of the peptides, reveal a general Atg8-binding sequence motif, and allow development of a more GABARAP-selective inhibitory peptide. These peptides effectively blocked autophagy when expressed in cultured cells. Expression of these ankyrin-derived peptides in Caenorhabditis elegans also inhibited autophagy, causing accumulation of the p62 homolog SQST-1, delayed development and shortened life span. Thus, these genetically encodable autophagy inhibitory peptides can be used to occlude autophagy spatiotemporally in living animals.

引用

页码：778 / 787

页数：10

共 50 条

[21] Neuron-specific isoform of brain ankyrin, 440-kD ankyrin(B), is targeted to the axons of rat cerebellar neurons [J].