Membrane structure-responsive lipid scrambling by TMEM63B to control plasma membrane lipid distribution

Yugo Miyata; Katsuya Takahashi; Yongchan Lee; Cheryl S Sultan; Risa Kuribayashi; Masatomo Takahashi; Kosuke Hata; Takeshi Bamba; Yoshihiro Izumi; Kehong Liu; Tomoko Uemura; Norimichi Nomura; So Iwata; Shigekazu Nagata; Tomohiro Nishizawa; Katsumori Segawa

doi:10.1038/s41594-024-01411-6

Membrane structure-responsive lipid scrambling by TMEM63B to control plasma membrane lipid distribution

Nat Struct Mol Biol. 2024 Oct 18. doi: 10.1038/s41594-024-01411-6. Online ahead of print.

Authors

Yugo Miyata^#^{1

2}, Katsuya Takahashi^#³, Yongchan Lee³, Cheryl S Sultan^{1

2}, Risa Kuribayashi^{1

2}, Masatomo Takahashi⁴, Kosuke Hata⁴, Takeshi Bamba⁴, Yoshihiro Izumi⁴, Kehong Liu⁵, Tomoko Uemura⁵, Norimichi Nomura⁵, So Iwata⁵, Shigekazu Nagata⁶, Tomohiro Nishizawa⁷, Katsumori Segawa^{8

9}

Affiliations

¹ Department of Medical Chemistry, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
² Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
³ Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan.
⁴ Division of Metabolomics, Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
⁵ Department of Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
⁶ Biochemistry and Immunology, World Premier International Research Center, Immunology Frontier Research Center, Osaka University, Osaka, Japan.
⁷ Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan. [email protected].
⁸ Department of Medical Chemistry, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan. [email protected].
⁹ Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. [email protected].

^# Contributed equally.

PMID: 39424995
DOI: 10.1038/s41594-024-01411-6

Abstract

Phospholipids are asymmetrically distributed in the plasma membrane (PM), with phosphatidylcholine and sphingomyelin abundant in the outer leaflet. However, the mechanisms by which their distribution is regulated remain unclear. Here, we show that transmembrane protein 63B (TMEM63B) functions as a membrane structure-responsive lipid scramblase localized at the PM and lysosomes, activating bidirectional lipid translocation upon changes in membrane curvature and thickness. TMEM63B contains two intracellular loops with palmitoylated cysteine residue clusters essential for its scrambling function. TMEM63B deficiency alters phosphatidylcholine and sphingomyelin distributions in the PM. Persons with heterozygous mutations in TMEM63B are known to develop neurodevelopmental disorders. We show that V44M, the most frequent substitution, confers constitutive scramblase activity on TMEM63B, disrupting PM phospholipid asymmetry. We determined the cryo-electron microscopy structures of TMEM63B in its open and closed conformations, uncovering a lipid translocation pathway formed in response to changes in the membrane environment. Together, our results identify TMEM63B as a membrane structure-responsive scramblase that controls PM lipid distribution and we reveal the molecular basis for lipid scrambling and its biological importance.