Cryo-EM structures of the caspase activated protein XKR9 involved in apoptotic lipid scrambling
- University of Zürich, Switzerland
Abstract
The exposure of the negatively charged lipid phosphatidylserine on the cell-surface, catalyzed by lipid scramblases, is an important signal for the clearance of apoptotic cells by macrophages. The protein XKR9 is a member of a conserved family that has been associated with apoptotic lipid scrambling. Here, we describe structures of full-length and caspase-treated XKR9 from Rattus norvegicus in complex with a synthetic nanobody determined by cryo-electron microscopy. The 43 kDa monomeric membrane protein can be divided into two structurally related repeats, each containing four membrane-spanning segments and a helix that is partly inserted into the lipid bilayer. In the full-length protein, the C-terminus interacts with a hydrophobic pocket located at the intracellular side acting as an inhibitor of protein function. Cleavage by caspase-3 at a specific site releases 16 residues of the C-terminus thus making the pocket accessible to the cytoplasm. Collectively, the work has revealed the unknown architecture of the XKR family and has provided initial insight into its activation by caspases.
Data availability
Coordinates have been deposited in the PDB under accession codes 7P14 and 7P16 and will be released upon publicationCryo-EM maps have been deposited in the EMBD under accession codes EMDB-13155 and EMDB-13157 and will be released upon publicationSource data files have been provided for Figure 1A-E,G, Figure 1-figure supplements 1 and 3B-D, Figure 2-figure supplements 1E and 2E.
Article and author information
Author details
Funding
European Research Council (ERC no 339116,AnoBest)
- Raimund Dutzler
Forschungskredit UZH (FK-20-040)
- Monique S Straub
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Janice L Robertson, Washington University in St Louis, United States
Version history
- Received: April 27, 2021
- Preprint posted: May 3, 2021 (view preprint)
- Accepted: July 11, 2021
- Accepted Manuscript published: July 15, 2021 (version 1)
- Version of Record published: July 22, 2021 (version 2)
Copyright
© 2021, Straub et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Cryo-EM structures of the caspase activated protein XKR9 involved in apoptotic lipid scrambling
eLife 10:e69800.
https://doi.org/10.7554/eLife.69800
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