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Extracellular calcium functions as a molecular glue for transmembrane helices to activate the scramblase Xkr4

Author

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  • Panpan Zhang

    (Kyoto University, Yoshida-Honmachi
    Kyoto University, Konoe-cho, Yoshida)

  • Masahiro Maruoka

    (Kyoto University, Yoshida-Honmachi
    Center for Integrated Biosystems, Institute for Biomedical Sciences, Academia Sinica)

  • Ryo Suzuki

    (Kyoto University, Yoshida-Honmachi)

  • Hikaru Katani

    (Kyoto University, Yoshida-Honmachi)

  • Yu Dou

    (Kyoto University, Yoshida-Honmachi
    Kyoto University, Konoe-cho, Yoshida)

  • Daniel M. Packwood

    (Kyoto University, Yoshida-Honmachi)

  • Hidetaka Kosako

    (Tokushima University)

  • Motomu Tanaka

    (Kyoto University, Yoshida-Honmachi
    Kyoto University, Yoshida-Honmachi
    Heidelberg University)

  • Jun Suzuki

    (Kyoto University, Yoshida-Honmachi
    Kyoto University, Konoe-cho, Yoshida
    Center for Integrated Biosystems, Institute for Biomedical Sciences, Academia Sinica
    CREST, Japan Science and Technology Agency)

Abstract

The “eat me” signal, phosphatidylserine is exposed on the surface of dying cells by phospholipid scrambling. Previously, we showed that the Xkr family protein Xkr4 is activated by caspase-mediated cleavage and binding of the XRCC4 fragment. Here, we show that extracellular calcium is an additional factor needed to activate Xkr4. The constitutively active mutant of Xkr4 is found to induce phospholipid scrambling in an extracellular, but not intracellular, calcium-dependent manner. Importantly, other Xkr family members also require extracellular calcium for activation. Alanine scanning shows that D123 and D127 of TM1 and E310 of TM3 coordinate calcium binding. Moreover, lysine scanning demonstrates that the E310K mutation-mediated salt bridge between TM1 and TM3 bypasses the requirement of calcium. Cysteine scanning proves that disulfide bond formation between TM1 and TM3 also activates phospholipid scrambling without calcium. Collectively, this study shows that extracellular calcium functions as a molecular glue for TM1 and TM3 of Xkr proteins for activation, thus demonstrating a regulatory mechanism for multi-transmembrane region-containing proteins.

Suggested Citation

  • Panpan Zhang & Masahiro Maruoka & Ryo Suzuki & Hikaru Katani & Yu Dou & Daniel M. Packwood & Hidetaka Kosako & Motomu Tanaka & Jun Suzuki, 2023. "Extracellular calcium functions as a molecular glue for transmembrane helices to activate the scramblase Xkr4," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40934-2
    DOI: 10.1038/s41467-023-40934-2
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    References listed on IDEAS

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    5. Rikinari Hanayama & Masato Tanaka & Keiko Miwa & Azusa Shinohara & Akihiro Iwamatsu & Shigekazu Nagata, 2002. "Identification of a factor that links apoptotic cells to phagocytes," Nature, Nature, vol. 417(6885), pages 182-187, May.
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    1. Han Niu & Masahiro Maruoka & Yuki Noguchi & Hidetaka Kosako & Jun Suzuki, 2024. "Phospholipid scrambling induced by an ion channel/metabolite transporter complex," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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