2023年新着論文 47　細胞情報学分野から論文が発表されました

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

Nat Commun. 2023 Sep 11;14(1):5592. doi: 10.1038/s41467-023-40934-2.

Authors

Panpan Zhang^1 2, Masahiro Maruoka^1 3, Ryo Suzuki⁴, Hikaru Katani¹, Yu Dou^1 2, Daniel M Packwood¹, Hidetaka Kosako⁵, Motomu Tanaka^{1 4 6}, Jun Suzuki^{7 8 9 10}

Affiliations

¹ Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Yoshida-Honmachi, Sakyoku, Kyoto, 606-8501, Japan.
² Graduate School of Biostudies, Kyoto University, Konoe-cho, Yoshida, Sakyoku, Kyoto, 606-8501, Japan.
³ Center for Integrated Biosystems, Institute for Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
⁴ Center for Integrative Medicine and Physics (CiMPhy), Institute for Advanced Study, Kyoto University, Yoshida-Honmachi, Sakyoku, Kyoto, 606-8501, Japan.
⁵ Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
⁶ Physical Chemistry of Biosystems, Institute of Physical Chemistry, Heidelberg University, 69120, Heidelberg, Germany.
⁷ Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Yoshida-Honmachi, Sakyoku, Kyoto, 606-8501, Japan. jsuzuki@icems.kyoto-u.ac.jp.
⁸ Graduate School of Biostudies, Kyoto University, Konoe-cho, Yoshida, Sakyoku, Kyoto, 606-8501, Japan. jsuzuki@icems.kyoto-u.ac.jp.
⁹ Center for Integrated Biosystems, Institute for Biomedical Sciences, Academia Sinica, Taipei, Taiwan. jsuzuki@icems.kyoto-u.ac.jp.
¹⁰ CREST, Japan Science and Technology Agency, Kawaguchi, Saitama, 332-0012, Japan. jsuzuki@icems.kyoto-u.ac.jp.

Free PMC article

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.

Conflict of interest statement

The authors declare no competing interests.

Full text links

カテゴリー: ニュース