Structural Basis for Autophagy Inhibition by the Human Rubicon–Rab7 Complex
Structural basis for autophagy inhibition by the human Rubicon–Rab7 complex Hersh K. Bhargavaa,b,1, Keisuke Tabatac, Jordan M. Bycka,b, Maho Hamasakid, Daniel P. Farrelle,f, Ivan Anishchenkoe,f, Frank DiMaioe,f, Young Jun Img, Tamotsu Yoshimoric,d, and James H. Hurleya,b,h,2 aDepartment of Molecular and Cell Biology, University of California, Berkeley, CA 94720; bCalifornia Institute for Quantitative Biosciences, University of California, Berkeley CA 94720; cDepartment of Genetics, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan; dLaboratory of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University, 565-0871 Osaka, Japan; eDepartment of Biochemistry, University of Washington, Seattle, WA 98195; fInstitute for Protein Design, University of Washington, Seattle, WA 98195; gCollege of Pharmacy, Chonnam National University, Gwangju, 61186, Republic of Korea; and hMolecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720 Edited by Brenda A. Schulman, Max Planck Institute of Biochemistry, Martinsried, Germany, and approved June 3, 2020 (received for review April 24, 2020) Rubicon is a potent negative regulator of autophagy and a autophagy regulators, which also includes PLEKHM1 and Pacer (9, potential target for autophagy-inducing therapeutics. Rubicon- 17), two other proteins that modulate late steps in autophagy. The mediated inhibition of autophagy requires the interaction of the RH domains of Rubicon, PLEKHM1, and Pacer all contain nine C-terminal Rubicon homology (RH) domain of Rubicon with Rab7– conserved cysteines and one conserved histidine, which have been GTP. Here we report the 2.8-Å crystal structure of the Rubicon RH predictedtobinddivalentzinccations and are required for Rubicon domain in complex with Rab7–GTP.
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