Kutlu Aslı, Çapkın Eda, Adacan Kaan, Yüce Meral
Istinye University, Faculty of Natural Science and Engineering, Department of Molecular Biology and Genetics, 34396 Istanbul, Türkiye.
Sabanci University, Faculty of Engineering and Natural Sciences, 34956 Istanbul, Türkiye.
ACS Omega. 2024 Nov 28;9(50):49272-49282. doi: 10.1021/acsomega.4c06318. eCollection 2024 Dec 17.
FcγRI plays a crucial role in the effector function of IgG antibodies, interacting with the lower hinge region of IgG1 with nanomolar affinity. Binding occurs specifically in domain 2 (D2) of the FcγRI ectodomain, while domain 3 (D3) is a flexible linker. The D3 domain is positioned away from the IgG binding site on the FcγRI and does not directly contact the Fc region. This study investigates the structural and functional properties of FcγRI D3 using 200 ns classical MD simulations of two models: (1) a full FcγRI ectodomain complex with Fc and (2) a truncated model excluding D3. Our findings suggest that the D3 ectodomain provides additional structural flexibility to the FcγRI-Fc complex without altering the C backbone motion or flexibility of the KHR binding motif in the FG loop. Critical residues involved in binding and contributing to complex stability were evaluated regarding changes in intramolecular interactions and destabilization tendency upon D3 truncation. Truncation did not significantly alter interactions around glycan-interacting residues in Fc chains or FcγRI-Fc binding interfaces. These findings provide valuable insights into the role of FcγRI D3 in modulating the structural dynamics of the FcγRI-Fc complex. While D3 does not directly contact Fc, its mobility and positioning may modulate the receptor's affinity, accessibility, and ability to bind IgG immune complexes. We suggest that a truncated FcγRI construct lacking the D3 domain may be a promising candidate for biosensor or capturing agents' development and optimization, offering improved performance in IgG capture assays without compromising critical binding interactions.
FcγRI在IgG抗体的效应功能中起关键作用，以纳摩尔亲和力与IgG1的下铰链区相互作用。结合特异性发生在FcγRI胞外域的结构域2（D2）中，而结构域3（D3）是一个柔性连接区。D3结构域远离FcγRI上的IgG结合位点，不直接接触Fc区域。本研究使用两个模型的200纳秒经典分子动力学模拟来研究FcγRI D3的结构和功能特性：（1）与Fc形成的完整FcγRI胞外域复合物；（2）排除D3的截短模型。我们的研究结果表明，D3胞外域为FcγRI-Fc复合物提供了额外的结构灵活性，而不会改变FG环中KHR结合基序的Cα主链运动或灵活性。通过D3截短后分子内相互作用的变化和去稳定化趋势，评估了参与结合并有助于复合物稳定性的关键残基。截短并没有显著改变Fc链或FcγRI-Fc结合界面中与聚糖相互作用残基周围的相互作用。这些发现为FcγRI D3在调节FcγRI-Fc复合物的结构动力学中的作用提供了有价值的见解。虽然D3不直接接触Fc，但其流动性和位置可能调节受体的亲和力、可及性以及结合IgG免疫复合物的能力。我们建议，缺乏D3结构域的截短FcγRI构建体可能是生物传感器或捕获剂开发与优化的有前途的候选者，在IgG捕获测定中可提供改进的性能，而不会损害关键的结合相互作用。
