Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720.
California Institute for Quantitative Biosciences, University of California, Berkeley CA 94720.
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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