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Structural basis for autophagy inhibition by the human Rubicon-Rab7 complex.


ABSTRACT: Rubicon is a potent negative regulator of autophagy and a potential target for autophagy-inducing therapeutics. Rubicon-mediated inhibition of autophagy requires the interaction of the C-terminal Rubicon homology (RH) domain of Rubicon with Rab7-GTP. Here we report the 2.8-Å crystal structure of the Rubicon RH domain in complex with Rab7-GTP. Our structure reveals a fold for the RH domain built around four zinc clusters. The switch regions of Rab7 insert into pockets on the surface of the RH domain in a mode that is distinct from those of other Rab-effector complexes. Rubicon residues at the dimer interface are required for Rubicon and Rab7 to colocalize in living cells. Mutation of Rubicon RH residues in the Rab7-binding site restores efficient autophagic flux in the presence of overexpressed Rubicon, validating the Rubicon RH domain as a promising therapeutic target.

SUBMITTER: Bhargava HK 

PROVIDER: S-EPMC7382272 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Structural basis for autophagy inhibition by the human Rubicon-Rab7 complex.

Bhargava Hersh K HK   Tabata Keisuke K   Byck Jordan M JM   Hamasaki Maho M   Farrell Daniel P DP   Anishchenko Ivan I   DiMaio Frank F   Im Young Jun YJ   Yoshimori Tamotsu T   Hurley James H JH  

Proceedings of the National Academy of Sciences of the United States of America 20200706 29


Rubicon is a potent negative regulator of autophagy and a potential target for autophagy-inducing therapeutics. Rubicon-mediated inhibition of autophagy requires the interaction of the C-terminal Rubicon homology (RH) domain of Rubicon with Rab7-GTP. Here we report the 2.8-Å crystal structure of the Rubicon RH domain in complex with Rab7-GTP. Our structure reveals a fold for the RH domain built around four zinc clusters. The switch regions of Rab7 insert into pockets on the surface of the RH dom  ...[more]

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