人源 Rubicon-Rab7 复合物抑制自噬的结构基础。
Structural basis for autophagy inhibition by the human Rubicon-Rab7 complex.
机构信息
Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720.
California Institute for Quantitative Biosciences, University of California, Berkeley CA 94720.
出版信息
Proc Natl Acad Sci U S A. 2020 Jul 21;117(29):17003-17010. doi: 10.1073/pnas.2008030117. Epub 2020 Jul 6.
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.
鲁比肯（Rubicon）是自噬的有效负调控因子，也是自噬诱导治疗的潜在靶点。Rubicon 介导的自噬抑制需要 Rubicon 的 C 末端 Rubicon 同源（RH）结构域与 Rab7-GTP 的相互作用。在这里，我们报告了 Rubicon RH 结构域与 Rab7-GTP 复合物的 2.8Å 晶体结构。我们的结构揭示了一种围绕四个锌簇构建的 RH 结构域折叠。Rab7 的开关区以与其他 Rab 效应物复合物不同的方式插入 RH 结构域表面的口袋中。二聚体界面处的 Rubicon 残基对于 Rubicon 和 Rab7 在活细胞中共定位是必需的。在表达过量 Rubicon 的情况下，Rab7 结合位点处 Rubicon RH 残基的突变恢复了有效的自噬通量，验证了 Rubicon RH 结构域作为有前途的治疗靶点的有效性。
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