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TitleThe role of the C-terminal tail region as a plug to regulate XKR8 lipid scramblase.
Journal, issue, pagesJ Biol Chem, Vol. 300, Issue 3, Page 105755, Year 2024
Publish dateFeb 15, 2024
AuthorsTakaharu Sakuragi / Ryuta Kanai / Mayumi Otani / Masahide Kikkawa / Chikashi Toyoshima / Shigekazu Nagata /
PubMed AbstractXK-related 8 (XKR8), in complex with the transmembrane glycoprotein basigin, functions as a phospholipid scramblase activated by the caspase-mediated cleavage or phosphorylation of its C-terminal ...XK-related 8 (XKR8), in complex with the transmembrane glycoprotein basigin, functions as a phospholipid scramblase activated by the caspase-mediated cleavage or phosphorylation of its C-terminal tail. It carries a putative phospholipid translocation path of multiple hydrophobic and charged residues in the transmembrane region. It also has a crucial tryptophan at the exoplasmic end of the path that regulates its scrambling activity. We herein investigated the tertiary structure of the human XKR8-basigin complex embedded in lipid nanodiscs at an overall resolution of 3.66 Å. We found that the C-terminal tail engaged in intricate polar and van der Waals interactions with a groove at the cytoplasmic surface of XKR8. These interactions maintained the inactive state of XKR8. Point mutations to disrupt these interactions strongly enhanced the scrambling activity of XKR8, suggesting that the activation of XKR8 is mediated by releasing the C-terminal tail from the cytoplasmic groove. We speculate that the cytoplasmic tail region of XKR8 functions as a plug to prevent the scrambling of phospholipids.
External linksJ Biol Chem / PubMed:38364890 / PubMed Central
MethodsEM (single particle)
Resolution3.66 Å
Structure data

EMDB-38291, PDB-8xej:
Cryo-EM structure of human XKR8-basigin complex in lipid nanodisc
Method: EM (single particle) / Resolution: 3.66 Å

Chemicals

ChemComp-DLP:
1,2-DILINOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / phospholipid*YM / Phosphatidylcholine

Source
  • homo sapiens (human)
  • oryctolagus cuniculus (rabbit)
KeywordsLIPID TRANSPORT / scramblase / apoptosis / membrane protein

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