Targeting the potent Beclin 1-UVRAG coiled-coil interaction with designed peptides enhances autophagy and endolysosomal trafficking.
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.
['Wu|Shuai|S|', 'He|Yunjiao|Y|', 'Qiu|Xianxiu|X|', 'Yang|Wenchao|W|', 'Liu|Wenchao|W|', 'Li|Xiaohua|X|', 'Li|Yan|Y|', 'Shen|Han-Ming|HM|', 'Wang|Renxiao|R|', 'Yue|Zhenyu|Z|', 'Zhao|Yanxiang|Y|0000-0002-9408-9979']
D000072283:A549 Cells D000595:Amino Acid Sequence D001343:Autophagy D000071186:Beclin-1 D002460:Cell Line D045744:Cell Line, Tumor D011992:Endosomes D066246:ErbB Receptors D057809:HEK293 Cells D006801:Humans D008247:Lysosomes D010455:Peptides D000072417:Protein Domains D054730:Protein Interaction Domains and Motifs D021381:Protein Transport D025521:Tumor Suppressor Proteins
autophagy endolysosomal trafficking Beclin 1 Atg14L UVRAG