Structural and mechanistic insights into regulation of the retromer coat by TBC1d5

Da Jia (), Jin-San Zhang, Fang Li, Jing Wang, Zhihui Deng, Mark A. White, Douglas G. Osborne, Christine Phillips-Krawczak, Timothy S. Gomez, Haiying Li, Amika Singla, Ezra Burstein, Daniel D. Billadeau () and Michael K. Rosen ()
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Da Jia: Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital and State Key Laboratory of Biotherapy, Sichuan University
Jin-San Zhang: Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic
Fang Li: Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital and State Key Laboratory of Biotherapy, Sichuan University
Jing Wang: Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital and State Key Laboratory of Biotherapy, Sichuan University
Zhihui Deng: Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic
Mark A. White: Sealy Center for Structural Biology, University of Texas Medical Branch
Douglas G. Osborne: Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic
Christine Phillips-Krawczak: Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic
Timothy S. Gomez: Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic
Haiying Li: UT Southwestern Medical Center
Amika Singla: UT Southwestern Medical Center
Ezra Burstein: UT Southwestern Medical Center
Daniel D. Billadeau: Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic
Michael K. Rosen: UT Southwestern Medical Center

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: Abstract Retromer is a membrane coat complex that is recruited to endosomes by the small GTPase Rab7 and sorting nexin 3. The timing of this interaction and consequent endosomal dynamics are thought to be regulated by the guanine nucleotide cycle of Rab7. Here we demonstrate that TBC1d5, a GTPase-activating protein (GAP) for Rab7, is a high-affinity ligand of the retromer cargo selective complex VPS26/VPS29/VPS35. The crystal structure of the TBC1d5 GAP domain bound to VPS29 and complementary biochemical and cellular data show that a loop from TBC1d5 binds to a conserved hydrophobic pocket on VPS29 opposite the VPS29–VPS35 interface. Additional data suggest that a distinct loop of the GAP domain may contact VPS35. Loss of TBC1d5 causes defective retromer-dependent trafficking of receptors. Our findings illustrate how retromer recruits a GAP, which is likely to be involved in the timing of Rab7 inactivation leading to membrane uncoating, with important consequences for receptor trafficking.

Date: 2016
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DOI: 10.1038/ncomms13305

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