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アディポネクチン受容体の構造的な洞察は,セラミダース活性を示唆する

Ieva Vasiliauskaité-Brooks¹, Remy Sounier¹, Pascal Rochaix¹

¹Institut de Génomique Fonctionnelle, CNRS UMR-5203 INSERM U1191, University of Montpellier, 34094 Montpellier, France.

|March 23, 2017

まとめ

アディポネクチン受容体 (ADIPORs) には固有のセラミダース活性がある. ADIPOR1とADIPOR2の異なるメカニズムは,構造と計算上の研究によって明らかになり,新しい治療モデュレータへの道を開いています.

科学分野:

生物化学
構造生物学
代謝疾患

背景:

アディポネクチン受容体 (ADIPORs) は,グルコースと脂質代謝の主要な調節体である.
ADIPORsはセラミダース活性を持ち,セラミドをスフィンゴシンと自由脂肪酸 (FFAs) に水解する.
ADIPORの機能の正確な分子メカニズムはほとんど不明です.

研究の目的:

ADIPOR1とADIPOR2の機能の分子メカニズムを解明する.
FFAに結合したADIPOR2の結晶構造を決定し,ADIPOR1の構造を修正する.
ADIPORsのセラミダース活性のためのメカニズムを提案する.

主な方法:

レセプター構造を決定するX線結晶学.
分子ダイナミクスシミュレーションを含む計算手法
セラミダースの活性を評価する生化学的測定法

主要な成果:

FFAに結合したADIPOR2の結晶構造は,アディポネクチンによって強化された固有のセラミダース活性を示しています.
ADIPOR2のセラミド結合姿勢と提案された水解機構の特定
改訂されたADIPOR1構造は,内在のセラミダース活性を持つ触媒部位を明らかにした独特の構造を示しています.
ADIPOR1とADIPOR2の機能的状態やメカニズムが異なることを示唆している.

結論:

ADIPOR1とADIPOR2は構造的特徴と固有のセラミダース活性が異なる.
この発見はADIPORの酵素メカニズムに関する洞察を与えてくれます.
これらの洞察は,代謝障害のための新しいADIPOR調節器の構造ベースの設計を導くことができます.

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