ArticleProceedings of the National Academy of Sciences of the United States of America2018
Targeting the potent Beclin 1-UVRAG coiled-coil interaction with designed peptides enhances autophagy and endolysosomal trafficking.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 64 citations in OpenAlex.
- The Beclin1‑Targeting stapled peptide suppresses colorectal cancer progression by disrupting EGFR/β-catenin axis.Journal of translational medicine · 2026Article
- Article
- Autophagy-Targeting Stapled Peptide Utilizes Macropinocytosis for Cell Entry to Potentiate Anti-Proliferative Autosis in Small-Cell Lung Cancer.Pharmaceutics · 2025Article
- The Potential of Peptide-Based Inhibitors in Disrupting Protein-Protein Interactions for Targeted Cancer Therapy.International journal of molecular sciences · 2025Review
- Beclin 1 prevents ISG15-mediated cytokine storms to secure fetal hematopoiesis and survival.The Journal of clinical investigation · 2025Article
- Structure-Activity Relationship Studies of an Autophagy Inhibitor That Targets the ATG14L-Beclin1 Protein-Protein Interaction Reveal Modifications That Improve Potency and Solubility and Maintain Selectivity.Journal of medicinal chemistry · 2025Article
- Structural insights into Beclin 1 interactions with it's regulators for autophagy modulation.Computational and structural biotechnology journal · 2025Review
- LOC730101 improves ovarian cancer drug sensitivity by inhibiting autophagy-mediated DNA damage repair via BECN1.Cell death & disease · 2024Article
- Regulatory Mechanisms Governing the Autophagy-Initiating VPS34 Complex and Its inhibitors.Biomolecules & therapeutics · 2024Review
- Total Synthesis of Lipopeptide Bacilotetrin C: Discovery of Potent Anticancer Congeners Promoting Autophagy.ACS medicinal chemistry letters · 2024Article
- Andrographolide acts with dexamethasone to inhibit the growth of acute lymphoblastic leukemia CEM‑C1 cells via the regulation of the autophagy‑dependent PI3K/AKT/mTOR signaling pathway.Biomedical reports · 2024Article
- UVRAG cooperates with cargo receptors to assemble the ER-phagy site.The EMBO journal · 2023Article
- Targeting autophagy and beyond: Deconvoluting the complexity of Beclin-1 from biological function to cancer therapy.Acta pharmaceutica Sinica. B · 2023Review
- Article
- The potent BECN2-ATG14 coiled-coil interaction is selectively critical for endolysosomal degradation of GPRASP1/GASP1-associated GPCRs.Autophagy · 2023Article
- Drug discovery by targeting the protein-protein interactions involved in autophagy.Acta pharmaceutica Sinica. B · 2023Review
- An autophagy-inducing stapled peptide induces mitochondria dysfunction and triggers autotic cell death in triple-negative breast cancer.Cell death discovery · 2023Article
- An autophagy-inducing stapled peptide promotes c-MET degradation and overrides adaptive resistance to sorafenib in c-METBiochemistry and biophysics reports · 2023Article
- Article
- Bi-Directional Relationship Between Autophagy and Inflammasomes in Neurodegenerative Disorders.Cellular and molecular neurobiology · 2023Review
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 4 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.