Targeting the potent Beclin 1-UVRAG coiled-coil interaction with designed peptides enhances autophagy and endolysosomal trafficking

Shuai Wu, Yunjiao He, Xianxiu Qiu, Wenchao Yang, Wenchao Liu, Xiaohua Li, Yan Li, Han Ming Shen, Renxiao Wang, Zhenyu Yue, Yanxiang Zhao

Research output: Journal article publicationJournal articleAcademic researchpeer-review

27 Citations (Scopus)


The Beclin 1-Vps34 complex, known as “mammalian class III PI3K,” plays essential roles in membrane-mediated transport processes including autophagy and endosomal trafficking. Beclin 1 acts as a scaffolding molecule for the complex and readily transits from its metastable homodimeric state to interact with key modulators such as Atg14L or UVRAG and form functionally distinct Atg14L/UVRAG-containing Beclin 1-Vps34 subcomplexes. The Beclin 1-Atg14L/ UVRAG interaction relies critically on their coiled-coil domains, but the molecular mechanism remains poorly understood. We determined the crystal structure of Beclin 1-UVRAG coiled-coil complex and identified a strengthened interface with both hydrophobic pairings and electrostatically complementary interactions. This structure explains why the Beclin 1-UVRAG interaction is more potent than the metastable Beclin 1 homodimer. Potent Beclin 1-UVRAG interaction is functionally significant because it renders UVRAG more competitive than Atg14L in Beclin 1 binding and is critical for promoting endolysosomal trafficking. UVRAG coiled-coil mutants with weakened Beclin 1 binding do not outcompete Atg14L and fail to promote endolysosomal degradation of the EGF receptor (EGFR). We designed all-hydrocarbon stapled peptides that specifically targeted the C-terminal part of the Beclin 1 coiled-coil domain to interfere with its homodimerization. One such peptide reduced Beclin 1 self-association, promoted Beclin 1-Atg14L/UVRAG interaction, increased autophagic flux, and enhanced EGFR degradation. Our results demonstrate that the targeting Beclin 1 coiled-coil domain with designed peptides to induce the redistribution of Beclin 1 among its self-associated form or Atg14L/UVRAG-containing complexes enhances both autophagy and endolysosomal trafficking.
Original languageEnglish
Pages (from-to)E5669-E5678
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number25
Publication statusPublished - 19 Jun 2018


  • Atg14L
  • Autophagy
  • Beclin 1
  • Endolysosomal trafficking

ASJC Scopus subject areas

  • General

Cite this