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Title: | Targeting the potent Beclin 1-UVRAG coiled-coil interaction with designed peptides enhances autophagy and endolysosomal trafficking | Authors: | Wu, S He, YJ Qiu, XX Yang, WC Liu, WC Li, XH Li, Y Shen, HM Wang, RX Yue, ZY Zhao, YX |
Issue Date: | 2018 | Source: | Proceedings of the National Academy of Sciences of the United States of America, 19 June 2018, v. 115, no. 25, p. E5669-E5678 | 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. | Keywords: | Beclin 1 UVRAG Atg14L Autophagy Endolysosomal trafficking |
Publisher: | National Academy of Sciences | Journal: | Proceedings of the National Academy of Sciences of the United States of America | ISSN: | 0027-8424 | EISSN: | 1091-6490 | DOI: | 10.1073/pnas.1721173115 | Rights: | © 2018 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/). The following publication Wu, S., He, Y., Qiu, X., Yang, W., Liu, W., Li, X., ... & Zhao, Y. (2018). Targeting the potent Beclin 1–UVRAG coiled-coil interaction with designed peptides enhances autophagy and endolysosomal trafficking. Proceedings of the National Academy of Sciences, 115(25), E5669-E5678 is available at https://doi.org/10.1073/pnas.1721173115 |
Appears in Collections: | Conference Paper |
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