Lactadherin’s Multistate Binding Predicts Stable Membrane-Bound Conformations of Factors V and VIII’s C Domains,Biochemistry

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Lactadherin’s Multistate Binding Predicts Stable Membrane-Bound Conformations of Factors V and VIII’s C Domains
Biochemistry ( IF 2.9 ) Pub Date : 2023-09-25 , DOI: 10.1021/acs.biochem.3c00274
Kevin J Cheng ₁ , Ashley M De Lio _{2,

3} , Riya Jain ₂ , Divyani Paul ₄ , James H Morrissey ₄ , Taras V Pogorelov _{1,

2,

5,

6}

Affiliation

Protein binding to negatively charged lipids is essential for maintaining numerous vital cellular processes where its dysfunction can lead to various diseases. One such protein that plays a crucial role in this process is lactadherin, which competes with coagulation factors for membrane binding sites to regulate blood clotting. Despite identifying key binding regions of these proteins through structural and biochemical studies, models incorporating membrane dynamics are still lacking. In this study, we report on the multimodal binding of lactadherin and use it to gain insight into the binding mechanisms of its C domain homologs, factor V and factor VIII. Molecular dynamics simulations enhanced with the highly mobile mimetic model enabled the determination of lactadherin’s multimodal binding on membranes that revealed critical interacting residues consistent with prior NMR and mutagenesis data. The binding occurred primarily via two dynamic structural ensembles: an inserted state and an unreported, highly conserved side-lying state driven by a cationic patch. We utilized these findings to analyze the membrane binding domains of coagulation factors V and VIII and identified their preferred membrane-bound conformations. Specifically, factor V’s C domains maintained an inserted state, while factor VIII preferred a tilted, side-lying state that permitted antibody binding. Insight into lactadherin’s atomistically resolved membrane interactions from a multistate perspective can guide new therapeutic opportunities in treating diseases related to blood coagulation.

中文翻译：

乳粘蛋白的多状态结合可预测因子 V 和 VIII 的 C 结构域的稳定膜结合构象

蛋白质与带负电荷的脂质结合对于维持许多重要的细胞过程至关重要，其中其功能障碍会导致各种疾病。在此过程中起关键作用的一种蛋白质是乳粘蛋白，它与凝血因子竞争膜结合位点以调节血液凝固。尽管通过结构和生化研究确定了这些蛋白质的关键结合区域，但仍然缺乏包含膜动力学的模型。在这项研究中，我们报告了乳粘蛋白的多模式结合，并使用它来深入了解其 C 结构域同源物、因子 V 和因子 VIII 的结合机制。使用高度可移动的模拟模型增强的分子动力学模拟能够确定乳粘蛋白在膜上的多模式结合，从而揭示了与先前的 NMR 和诱变数据一致的关键相互作用残基。结合主要通过两个动态结构集合发生：插入状态和由阳离子补丁驱动的未报道的、高度保守的侧躺状态。我们利用这些发现来分析凝血因子 V 和 VIII 的膜结合结构域，并确定了它们首选的膜结合构象。具体来说，因子 V 的 C 结构域保持插入状态，而因子 VIII 更喜欢允许抗体结合的倾斜侧躺状态。从多状态角度深入了解乳粘蛋白原子分辨的膜相互作用，可以指导治疗凝血相关疾病的新治疗机会。

更新日期：2023-09-25

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