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Improved mammalian retromer cryo-EM structures reveal a new assembly interface

View ORCID ProfileAmy K. Kendall, View ORCID ProfileMintu Chandra, Boyang Xie, View ORCID ProfileWilliam Wan, View ORCID ProfileLauren P. Jackson
doi: https://doi.org/10.1101/2022.03.04.482375
Amy K. Kendall
1Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA
2Center for Structural Biology, Vanderbilt University, Nashville, TN, USA
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Mintu Chandra
1Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA
2Center for Structural Biology, Vanderbilt University, Nashville, TN, USA
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Boyang Xie
1Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA
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William Wan
2Center for Structural Biology, Vanderbilt University, Nashville, TN, USA
3Department of Biochemistry, Vanderbilt University, Nashville, TN, USA
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Lauren P. Jackson
1Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA
2Center for Structural Biology, Vanderbilt University, Nashville, TN, USA
3Department of Biochemistry, Vanderbilt University, Nashville, TN, USA
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  • For correspondence: lauren.p.jackson@vanderbilt.edu
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Abstract

Retromer (VPS26/VPS35/VPS29 subunits) assembles with multiple sorting nexin (SNX) proteins on membranes to mediate endosomal recycling of transmembrane protein cargoes. Retromer has been implicated in other cellular events, including mitochondrial homeostasis, nutrient sensing, autophagy, and fission events. Mechanisms for mammalian retromer assembly remain undefined, and retromer engages multiple sorting nexin proteins to sort cargoes to different destinations. Published structures demonstrate mammalian retromer forms oligomers in vitro, but several structures were poorly resolved. We report here improved retromer oligomer structures using single particle cryo-electron microscopy (cryo-EM) by combining data collected from tilted specimens with multiple improvements in data processing, including using a three-dimensional (3D) starting model for improved automated particle picking in RELION. A retromer mutant (3KE retromer) that breaks VPS35-mediated interfaces was used to determine a structure of a new assembly interface formed by the VPS26A and VPS35 N-termini. The interface reveals how an N-terminal VPS26A arrestin saddle can link retromer chains by engaging a neighboring VPS35 N-terminus, on the opposite side from the well-characterized C-VPS26/N-VPS35 interaction observed within heterotrimers. The new interaction interface exhibits substantial buried surface area (∼7,000 Å2) and further suggests metazoan retromer may serve as an adaptable scaffold.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 04, 2022.
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Improved mammalian retromer cryo-EM structures reveal a new assembly interface
Amy K. Kendall, Mintu Chandra, Boyang Xie, William Wan, Lauren P. Jackson
bioRxiv 2022.03.04.482375; doi: https://doi.org/10.1101/2022.03.04.482375
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Improved mammalian retromer cryo-EM structures reveal a new assembly interface
Amy K. Kendall, Mintu Chandra, Boyang Xie, William Wan, Lauren P. Jackson
bioRxiv 2022.03.04.482375; doi: https://doi.org/10.1101/2022.03.04.482375

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