An agent-based approach for modelling and simulation of glycoprotein VI receptor diffusion, localisation and dimerisation in platelet lipid rafts.
An agent-based approach for modelling and simulation of glycoprotein VI receptor diffusion, localisation and dimerisation in platelet lipid rafts.
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DOI：
10.1038/s41598-023-30884-6
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发表时间：
2023-03-08
影响因子：
4.6
通讯作者：
Gibbins, Jonathan M.
中科院分区：
文献类型：
--
作者：
Tantiwong, Chukiat;Dunster, Joanne L.;Cavill, Rachel;Tomlinson, Michael G.;Wierling, Christoph;Heemskerk, Johan W. M.;Gibbins, Jonathan M.
受体扩散通过质膜微环境和受体相互作用在细胞信号传导中起着至关重要的作用，但其调控机制尚不清楚。为了帮助理解受体扩散和信号传导的关键决定因素，我们开发了基于agent的模型（ABMs）来探索血小板和巨核细胞特异性胶原糖蛋白VI （GPVI）受体二聚化的程度。该方法评估了质膜内富含糖脂的筏状结构域降低受体扩散率的重要性。我们的模型模拟表明，GPVI二聚体优先集中在受限区域，如果区域内的扩散率相对于区域外的扩散率降低，二聚化率就会增加。虽然限制结构域数量的增加导致了进一步的二聚化，但在膜重排时可能发生的结构域合并却没有效果。对构成脂筏的细胞膜比例的建模表明，二聚化水平不能单独用这些来解释。其他膜蛋白对受体的拥挤也是GPVI二聚化的重要决定因素。总之，这些结果证明了ABM方法在探索细胞表面相互作用方面的价值，指导了新的治疗途径的实验。
Receptor diffusion plays an essential role in cellular signalling via the plasma membrane microenvironment and receptor interactions, but the regulation is not well understood. To aid in understanding of the key determinants of receptor diffusion and signalling, we developed agent-based models (ABMs) to explore the extent of dimerisation of the platelet- and megakaryocyte-specific receptor for collagen glycoprotein VI (GPVI). This approach assessed the importance of glycolipid enriched raft-like domains within the plasma membrane that lower receptor diffusivity. Our model simulations demonstrated that GPVI dimers preferentially concentrate in confined domains and, if diffusivity within domains is decreased relative to outside of domains, dimerisation rates are increased. While an increased amount of confined domains resulted in further dimerisation, merging of domains, which may occur upon membrane rearrangements, was without effect. Modelling of the proportion of the cell membrane which constitutes lipid rafts indicated that dimerisation levels could not be explained by these alone. Crowding of receptors by other membrane proteins was also an important determinant of GPVI dimerisation. Together, these results demonstrate the value of ABM approaches in exploring the interactions on a cell surface, guiding the experimentation for new therapeutic avenues.
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