価値創造研究センター外国人客員教員Cheng先生（太田研究室受け入れ）による講演会が行われます。ご興味のある方は是非ご参加ください。なお、事前登録の必要はありません。

■日時
2024年6月17日（月）14:45-16:15　参加自由
■場所
情報学棟４F　第5講義室
■講演者　
Cheng Xiaolin先生（オハイオ州立大学　薬学部　教授）
■問合せ先
価値創造研究センター事務室　内線4247
office-fvcrcnu@t.mail.nagoya-u.ac.jp　　
　　　
■題目
Structural Mechanisms of SCAP Activation Mediated by Ammonia

■概要
Cholesterol homeostasis is regulated by the sterol regulatory element-binding protein (SREBP) pathway. with the membrane-embedded SREBP-cleavage-activating protein (SCAP) and insulin-inducible gene protein (Insig)-1/2 acting as sterol sensors. Our previous work revealed the critical role of ammonia in activating the SREBP pathway and identified a potential ammonia binding site formed by D428, S326 and S330 located at the core of the SCAP transmembrane domain1. In this presentation, I will discuss our recent molecular dynamics (MD) simulation study that elucidates the structural mechanisms by which ammonia binding may stimulate SCAP/Insig dissociation and SREBP activation. The SCAP S4 helix is thought to undergo a dynamic interconversion between two conformations: a partially unfolded, bent (inactive) state and a fully intact, straight (active) state during SCAP activation. Our simulations suggest that ammonia acts as an agonist of SCAP, while 25-hydroxycholesterol (25-HC) functions as an antagonist, stabilizing the active and inactive states of SCAP, respectively. Notably, ammonia operates as a hinge connecting the S3 and S6 helices, facilitating their coordinated movement. This hinge is critical for propagating the conformational transition of the S4 helix throughout the SCAP transmembrane domain, inducing alterations in the orientation and structure of the S3 and S6 helices. These structural changes lead to a decreased interaction interface contact area between SCAP and Insig and the repositioned MELADL motif at the membrane surface. Collectively, our findings reveal the intricate interplay between 25-HC and ammonia binding and the conformational transition of the SCAP S4 helix, underscoring the pivotal role of the S4 helix in SCAP activation.
1. Cheng C, Geng F, Li Z, Zhong Y, Wang H, Cheng X, Zhao Y, Mo X, Horbinski C, Duan W, Chakravarti A, Cheng X & Guo D. Ammonia stimulates SCAP/Insig dissociation and SREBP-1 activation to promote lipogenesis and tumour growth. Nature metabolism. 2022 May;4(5):575-88.