Elucidation of the formation mechanism on glycolipid-protein assemblages in lipid rafts

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K05713
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 37020:Chemistry and chemical methodology of biomolecules-related
• Research Institution: Tottori University (2022); Osaka University (2019-2021)
• Principal Investigator: Hanashima Shinya 鳥取大学, 工学研究科, 教授 (50373353)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: 糖脂質 / 脂質ラフト / NMR / 相互作用 / NMR

Outline of Final Research Achievements

We examined the lateral interaction between the transmembrane domain of the EGF receptor and ganglioside GM3 in the lipid membranes. The fluorescently labeled EGF receptor transmembrane domain was chemically synthesized and reconstituted into bilayer membranes with GM3 and other phospholipids. FRET and fluorescence quenching experiments revealed that GM3 interacts with the EGF receptor transmembrane domain to stabilize the monomer. Solid-state NMR experiments using isotope-labeled GM3 probes revealed that the orientation of the GM3 head group on the lipid membrane was slightly altered by different membrane lipid compositions and cholesterol concentrations. We showed that small structural changes in the GM3 head group caused by the membrane environment may affect interactions with membrane proteins, such as EGF receptors, and thus affect the association state and activity of membrane proteins.

Free Research Field

生物有機化学

Academic Significance and Societal Importance of the Research Achievements

側方的な脂質とタンパク質相互作用の解析法を確立し、これまで複雑な膜組成を有する細胞を用いた実験でしか示されてこなかった、脂質膜外葉のGM３とEGF受容体膜ドメインの直接的な相互作用をモデル系で初めて検出した。この相互作用はGM3選択的に起こっており、糖脂質選択性はタンパク質の配列依存的である可能性がある。このような膜タンパク質の活性を制御する脂質の側方的な相互作用を制御できる化合物は、EGF受容体が関連する疾患の新しい創薬リード化合物となる可能性もある。