Bruno Michael J, Koeppe Roger E, Andersen Olaf S
Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY 10021, USA.
Proc Natl Acad Sci U S A. 2007 Jun 5;104(23):9638-43. doi: 10.1073/pnas.0701015104. Epub 2007 May 29.
At low micromolar concentrations, polyunsaturated fatty acids (PUFAs) alter the function of many membrane proteins. PUFAs exert their effects on unrelated proteins at similar concentrations, suggesting a common mode of action. Because lipid bilayers serve as the common "solvent" for membrane proteins, the common mechanism could be that PUFAs adsorb to the bilayer/solution interface to promote a negative-going change in lipid intrinsic curvature and, like other reversibly adsorbing amphiphiles, increase bilayer elasticity. PUFA adsorption thus would alter the bilayer deformation energy associated with protein conformational changes involving the protein/bilayer boundary, which would alter protein function. To explore the feasibility of such a mechanism, we used gramicidin (gA) analogues of different lengths together with bilayers of different thicknesses to assess whether docosahexaenoic acid (DHA) could exert its effects through a bilayer-mediated mechanism. Indeed, DHA increases gA channel appearance rates and lifetimes and decreases the free energy of channel formation. The appearance rate and lifetime changes increase with increasing channel-bilayer hydrophobic mismatch and are not related to differing DHA bilayer absorption coefficients. DHA thus alters bilayer elastic properties, not just lipid intrinsic curvature; the elasticity changes are important for DHA's bilayer-modifying actions. Oleic acid (OA), which has little effect on membrane protein function, exerts no such effects despite OA's adsorption coefficient being an order of magnitude greater than DHA's. These results suggest that DHA (and other PUFAs) may modulate membrane protein function by bilayer-mediated mechanisms that do not involve specific protein binding but rather changes in bilayer material properties.
在低微摩尔浓度下，多不饱和脂肪酸（PUFAs）会改变许多膜蛋白的功能。PUFAs在相似浓度下对不相关的蛋白发挥作用，这表明存在一种共同的作用模式。由于脂质双层是膜蛋白的共同“溶剂”，其共同机制可能是PUFAs吸附到双层/溶液界面，促进脂质固有曲率向负向变化，并且与其他可逆吸附的两亲分子一样，增加双层弹性。因此，PUFA吸附会改变与涉及蛋白质/双层边界的蛋白质构象变化相关的双层变形能，进而改变蛋白质功能。为了探究这种机制的可行性，我们使用了不同长度的短杆菌肽（gA）类似物以及不同厚度的双层膜，以评估二十二碳六烯酸（DHA）是否能通过双层介导的机制发挥作用。事实上，DHA增加了gA通道的出现率和寿命，并降低了通道形成的自由能。出现率和寿命的变化随着通道-双层疏水不匹配的增加而增加，且与不同的DHA双层吸收系数无关。因此，DHA改变的是双层弹性特性，而不仅仅是脂质固有曲率；弹性变化对于DHA的双层修饰作用很重要。油酸（OA）对膜蛋白功能几乎没有影响，尽管OA的吸附系数比DHA的大一个数量级，但它并没有产生这样的效果。这些结果表明，DHA（以及其他PUFAs）可能通过双层介导的机制调节膜蛋白功能，这种机制不涉及特定的蛋白质结合，而是双层材料特性的变化。
