Characterization of interaction between blood coagulation factor VIII and LRP1 suggests dynamic binding by alternating complex contacts.
Characterization of interaction between blood coagulation factor VIII and LRP1 suggests dynamic binding by alternating complex contacts.
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DOI：
10.1111/jth.15817
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发表时间：
2022-10
影响因子：
10.4
通讯作者：
Sarafanov, Andrey G.
中科院分区：
文献类型：
--
作者：
Chun, Haarin;Kurasawa, James H.;Olivares, Philip;Marakasova, Ekaterina S.;Shestopal, Svetlana A.;Hassink, Gabriela U.;Karnaukhova, Elena;Migliorini, Mary;Obi, Juliet O.;Smith, Ally K.;Wintrode, Patrick L.;Durai, Prasannavenkatesh;Park, Keunwan;Deredge, Daniel;Strickland, Dudley K.;Sarafanov, Andrey G.
关键词：
凝血因子 VIII (FVIII) 缺乏会导致危及生命的出血（血友病 A），可通过输注 FVIII 浓缩物进行治疗。为了改善疾病治疗，FVIII 已被修饰以延长其血浆半衰期，这需要了解 FVIII 分解代谢的机制。肝脏低密度脂蛋白受体相关蛋白 1 (LRP1) 是一个重要的分解代谢因子，它还调节许多其他具有临床意义的过程。先前的研究表明 FVIII 结合 LRP1 位点的复杂性。表征 FVIII 和 LRP1 之间的结合位点并提出相互作用模型。在杆状病毒系统中生成了一系列 LRP1 的重组配体结合补体型重复 (CR) 片段，包括突变变体，并使用表面等离子共振、组织培养模型、氢-氘交换质谱和计算机测试了 FVIII 相互作用。 LRP1 簇 II 和 IV 内的多个 CR 双联体被确定为替代的 FVIII 结合位点。这些相互作用遵循提供主要结合能的规范结合模式，而额外的弱相互作用由相邻的 CR 结构域贡献。代表性的 CR 双联体显示在 FVIII 上有多个接触位点。 FVIII 和 LRP1 通过形成涉及规范和非规范结合组合的多个复杂接触来相互作用。我们提出 FVIII-LRP1 相互作用是通过以动态模式切换此类替代结合组合来发生的，并且该机制与包括 LRP1 在内的低密度脂蛋白受体家族成员的其他配体相互作用相关。
Deficiency in blood coagulation factor VIII (FVIII) results in life‐threating bleeding (hemophilia A) treated by infusions of FVIII concentrates. To improve disease treatment, FVIII has been modified to increase its plasma half‐life, which requires understanding mechanisms of FVIII catabolism. An important catabolic actor is hepatic low density lipoprotein receptor‐related protein 1 (LRP1), which also regulates many other clinically significant processes. Previous studies showed complexity of FVIII site for binding LRP1. To characterize binding sites between FVIII and LRP1 and suggest a model of the interaction. A series of recombinant ligand‐binding complement‐type repeat (CR) fragments of LRP1 including mutated variants was generated in a baculovirus system and tested for FVIII interaction using surface plasmon resonance, tissue culture model, hydrogen–deuterium exchange mass spectrometry, and in silico. Multiple CR doublets within LRP1 clusters II and IV were identified as alternative FVIII‐binding sites. These interactions follow the canonical binding mode providing major binding energy, and additional weak interactions are contributed by adjacent CR domains. A representative CR doublet was shown to have multiple contact sites on FVIII. FVIII and LRP1 interact via formation of multiple complex contacts involving both canonical and non‐canonical binding combinations. We propose that FVIII‐LRP1 interaction occurs via switching such alternative binding combinations in a dynamic mode, and that this mechanism is relevant to other ligand interactions of the low‐density lipoprotein receptor family members including LRP1.
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影响因子：
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DOI：
10.1016/j.jbc.2021.100715
发表时间：
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期刊：
The Journal of biological chemistry
影响因子：
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