PDF(Pubmed)
Abstract：
TRIM21 is a pivotal effector in the immune system, orchestrating antibody-mediated responses and modulating immune signaling. In this comprehensive study, we focus on the interaction of TRIM21 with Fc engineered antibodies and subsequent implications for viral neutralization. Through a series of analytical techniques, including biosensor assays, mass photometry, and electron microscopy, along with structure predictions, we unravel the intricate mechanisms governing the interplay between TRIM21 and antibodies. Our investigations reveal that the TRIM21 capacity to recognize, bind, and facilitate the proteasomal degradation of antibody-coated viruses is critically dependent on the affinity and avidity interplay of its interactions with antibody Fc regions. We suggest a novel binding mechanism, where TRIM21 binding to one Fc site results in the detachment of PRYSPRY from the coiled-coil domain, enhancing mobility due to its flexible linker, thereby facilitating the engagement of the second site, resulting in avidity due to bivalent engagement. These findings shed light on the dual role of TRIM21 in antiviral immunity, both in recognizing and directing viruses for intracellular degradation, and demonstrate its potential for therapeutic exploitation. The study advances our understanding of intracellular immune responses and opens new avenues for the development of antiviral strategies and innovation in tailored effector functions designed to leverage TRIM21s unique binding mode.
摘要：
TRIM21是免疫系统中的关键效应物,协调抗体介导的反应和调节免疫信号。在这项全面的研究中，我们专注于TRIM21与Fc工程化抗体的相互作用以及随后对病毒中和的影响。通过一系列分析技术，包括生物传感器检测，质量测光,和电子显微镜，以及结构预测，我们解开了控制TRIM21和抗体之间相互作用的复杂机制。我们的调查显示，TRIM21识别能力，绑定,和促进抗体包被的病毒的蛋白酶体降解关键依赖于其与抗体Fc区相互作用的亲和力和亲合力相互作用。我们提出了一种新的结合机制，其中TRIM21与一个Fc位点的结合导致PRYSPRY从卷曲螺旋结构域脱离，由于其灵活的接头，增强了移动性，从而促进第二站点的参与，由于二价参与而产生亲合力。这些发现揭示了TRIM21在抗病毒免疫中的双重作用，在识别和指导病毒细胞内降解方面，并展示了其治疗开发的潜力。该研究促进了我们对细胞内免疫反应的理解，并为开发抗病毒策略和创新设计以利用TRIM21s独特结合模式的定制效应子功能开辟了新的途径。
