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题目(Title):
De novo design of functional membrane proteins
主讲人(Speaker):
卢培龙
开始时间(Start Time):
2025-07-02 13:30
结束时间(End Time):
报告地点(Place):
生命学院L楼报告厅
主办单位(Organization):
生命科学与技术学院
协办单位(Co-organizer):
简介(Brief Introduction):
Transmembrane proteins facilitate the exchange of materials, energy, and information across the cell membrane, thereby enabling cells to adapt more effectively to the surrounding environment. There has been de novo designed transmembrane proteins; however, they lack the ability to respond to specific environmental cues—such as voltage, pH, ligands, mechanical force, light, and temperature. Here, we report the de novo design of voltage-gated anion channels (VGAC) and transmembrane fluorescence-activating proteins (tmFAP). VGACs adopt a 15-helix pentameric structure featuring a constriction composed of five arginine residues within the transmembrane span. In patch-clamp experiments, VGACs displayed strictly voltage-dependent currents and demonstrated selectivity for chloride anions over iodide anions. Our data suggest that the arginine constriction undergoes voltage-induced conformational changes, serving as both the voltage sensor and selectivity filter. tmFAPs possess pre-organized ligand-binding pockets in high-quality 4-helix backbones for a fluorogenic ligand, and specifically activate the fluorescence of the target fluorophore with mid-nanomolar affinity, exhibiting higher brightness and quantum yield compared to EGFP. VGACs and tmFAPs function effectively in mammalian cells upon expression. Cryo-EM and crystal structures of the designed transmembrane proteins show a high degree of agreement with our design models. Collectively, our results provide novel insights into membrane biology and open avenues for a diverse array of applications.