5YR0

Structure of Beclin1-UVRAG coiled coil domain complex

Summary for 5YR0

• Entry DOI: 10.2210/pdb5yr0/pdb
• Descriptor: Beclin-1, UV radiation resistance associated protein (3 entities in total)
• Functional Keywords: autophagy regulator, endocytosis
• Biological source: Mus musculus (Mouse); More
• Total number of polymer chains: 2
• Total formula weight: 11589.12

Authors

Pan, X.,Zhao, Y.,He, Y. (deposition date: 2017-11-08, release date: 2018-06-13, Last modification date: 2024-03-27)

Primary citation

Wu, S.,He, Y.,Qiu, X.,Yang, W.,Liu, W.,Li, X.,Li, Y.,Shen, H.M.,Wang, R.,Yue, Z.,Zhao, Y.
Targeting the potent Beclin 1-UVRAG coiled-coil interaction with designed peptides enhances autophagy and endolysosomal trafficking.
Proc. Natl. Acad. Sci. U.S.A., 115:E5669-E5678, 2018

PubMed 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.

PubMed: 29866835
DOI: 10.1073/pnas.1721173115

Experimental method

X-RAY DIFFRACTION (1.9 Å)