2023 Fiscal Year Final Research Report
Elucidation of the molecular mechanism of scramblase, and the substrate specificity of flippase
Project/Area Number |
21H04770
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Research Category |
Grant-in-Aid for Scientific Research (A)
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Allocation Type | Single-year Grants |
Section | 一般 |
Review Section |
Medium-sized Section 43:Biology at molecular to cellular levels, and related fields
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Research Institution | Osaka University |
Principal Investigator |
NAGATA Shigekazu 大阪大学, 免疫学フロンティア研究センター, 特任教授(常勤) (70114428)
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Co-Investigator(Kenkyū-buntansha) |
瀬川 勝盛 東京医科歯科大学, 難治疾患研究所, 教授 (20542971)
櫻木 崇晴 大阪大学, 免疫学フロンティア研究センター, 特任助教(常勤) (10867906)
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Project Period (FY) |
2021-04-05 – 2024-03-31
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Keywords | フリッパーゼ / スクランブラーゼ / リン脂質 / 三次構造 / 基質特異性 |
Outline of Final Research Achievements |
In this study, we aimed to elucidate the physiological function of flippases (ATP11A and ATP11C) and scramblases (TMEM16F and XKR8), as well as their molecular mechanisms of action. The following results were obtained: (1) Syncytiotrophoblasts were underdeveloped in the placentas of ATP11A-deficient mice, leading to embryonic death. (2) We discovered that a point mutation in the ATP11A gene in a Japanese patient with a neurological disorder alters substrate specificity. (3) Using CryEM techniques, we determined the tertiary structure of human XKR8 and suggested the possibility of phospholipids passing through the lipid bilayer via hydrophilic amino acids inside the XKR8 molecule. (4) We observed the involvement of XK, a paralog of XKR8, in the process of exposing phosphatidylserine in inflamed tissues in response to high concentrations of ATP.
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Free Research Field |
生化学
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Academic Significance and Societal Importance of the Research Achievements |
研究代表者はリン脂質の非対称性を維持するための酵素、それを崩壊するための分子を同定してきた。本研究ではXKR8スクランブラーゼの3次構造を明らかにし、この分子が親水性の頭部を持つリン脂質に通り道を提供していることを示した。また、フリッパーゼの点変異がリン脂質の基質特異性を変化させ、ヒトに重篤な神経疾患をもたらすこと、その遺伝子欠損は胎盤合胞体の発達不全をもたらすことを示した。これらの成果は難治性神経疾患、不妊症など理解する上でも有用であろう。
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