Schmitt Janika, Poole Emma, Groves Ian, Owen David J, Graham Stephen C, Sinclair John, Kelly Bernard T
Department of Medicine, Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Hills Road, CB2 0SP, Cambridge, UK.
Faculty of Medicine, Charité Berlin, 10117, Berlin, Germany.
EMBO Rep. 2024 Mar;25(3):951-970. doi: 10.1038/s44319-024-00063-3. Epub 2024 Jan 29.
The exquisite specificity of antibodies can be harnessed to effect targeted degradation of membrane proteins. Here, we demonstrate targeted protein removal utilising a protein degradation domain derived from the endogenous human protein Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9). Recombinant antibodies genetically fused to this domain drive the degradation of membrane proteins that undergo constitutive internalisation and recycling, including the transferrin receptor and the human cytomegalovirus latency-associated protein US28. We term this approach PACTAC (PCSK9-Antibody Clearance-Targeting Chimeras).
抗体的高度特异性可用于实现膜蛋白的靶向降解。在此，我们展示了利用源自内源性人类蛋白前蛋白转化酶枯草杆菌蛋白酶/克新蛋白酶9型（PCSK9）的蛋白质降解结构域进行靶向蛋白质清除。与该结构域基因融合的重组抗体可驱动经历组成型内化和再循环的膜蛋白降解，包括转铁蛋白受体和人类巨细胞病毒潜伏相关蛋白US28。我们将这种方法称为PACTAC（PCSK9-抗体清除-靶向嵌合体）。
