Lipid modulation of protein-induced membrane domains as a mechanism for controlling signal transduction
Lipid modulation of protein-induced membrane domains as a mechanism for controlling signal transduction
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DOI：
10.1021/bi036334t
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发表时间：
2004-06-08
期刊：
影响因子：
2.9
通讯作者：
Almeida, PFF
中科院分区：
文献类型：
--
作者：
Hinderliter, A;Biltonen, RL;Almeida, PFF
真核细胞膜中存在巨大脂质多样性的原因在很大程度上仍然是一个谜。我们认为它的作用是为膜水平的信号事件提供开关。这是通过脂质-脂质相互作用来实现的，该相互作用将膜蛋白结合和缔合事件转化为非常合作的过程，同时保持可逆性。我们之前已经展示了 [Hinderliter，A.，等人。 (2001) Biochemistry 40, 4181-4191]脂质分层的内在趋势和混合物中蛋白质与特定脂质的优先相互作用之间的热力学联系导致脂质和蛋白质结构域形成的巨大变化。在这里，我们测试了这样的假设：脂质化学结构的微小变化会以可预测的方式改变不同脂质之间的净相互作用自由能 (omega(AB)) 的大小，并且当与蛋白质结合结合时，即使 omega(AB) 非常小的变化也会导致双层组织发生巨大变化。我们通过改变 PC 酰基链长度和不饱和度，系统地改变了磷脂酰胆碱 (PC) 与固定磷脂酰丝氨酸 (PS) 的混合物的化学结构，并检查了添加外周蛋白（突触结合蛋白 I C2A 基序）后的结构域形成。使用蒙特卡罗计算机模拟解释了模拟 PS 的芘取代脂质的实验准分子/单体比率 (E/M)。如果 PC 熔化温度较低，E/M 较大，这表明域的形成是 PC 和 PS 之间弱相互作用的热力学结果。与我们的假设一致，只需要 omega(AB) 的非常小的变化就可以预测脂质和蛋白质结构域形成的巨大变化。
The reason for the enormous lipid variety present in eukaryotic membranes remains largely an enigma. We suggest that its role is to provide an on-off switch for a signaling event at the membrane level. This is achieved through lipid-lipid interactions that convert membrane protein binding and association events into very cooperative processes while maintaining reversibility. We have previously shown [Hinderliter, A., at al. (2001) Biochemistry 40, 4181-4191] that thermodynamic linkage between an intrinsic tendency for lipid demixing and a preferential interaction of a protein with a specific lipid within the mixture leads to dramatic changes in lipid and protein domain formation. Here, we tested the hypothesis that small alterations in lipid chemical structure alter the magnitude of the net interaction free energy (omega(AB)) between unlike lipids in a predictable manner, and that even very small changes in omega(AB) lead to dramatic changes in bilayer organization when coupled with protein binding. We systematically varied the chemical structure of phosphatidylcholine (PC), in mixtures with a fixed phosphatidylserine (PS), by changing the PC acyl chain length and the degree of unsaturation, and examined domain formation upon addition of a peripheral protein, the synaptotagmin I C2A motif. Experimental excimer/monomer ratios (E/M) of pyrene-substituted lipids mimicking the PS were interpreted using Monte Carlo computer simulations. E/M is larger if the PC melting temperature is lower, suggesting that domain formation is a thermodynamic consequence of weak interactions between PC and PS. Consistent with our hypothesis, only very small changes in omega(AB) were required for prediction of large changes in lipid and protein domain formation.