Gay Austin, Rye Daphne, Radhakrishnan Arun
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas.
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas.
Biophys J. 2015 Mar 24;108(6):1459-1469. doi: 10.1016/j.bpj.2015.02.008.
Many cellular processes are sensitive to levels of cholesterol in specific membranes and show a strongly sigmoidal dependence on membrane composition. The sigmoidal responses of the cholesterol sensors involved in these processes could arise from several mechanisms, including positive cooperativity (protein effects) and limited cholesterol accessibility (membrane effects). Here, we describe a sigmoidal response that arises primarily from membrane effects due to sharp changes in the chemical activity of cholesterol. Our models for eukaryotic membrane-bound cholesterol sensors are soluble bacterial toxins that show an identical switch-like specificity for endoplasmic reticulum membrane cholesterol. We show that truncated versions of these toxins fail to form oligomers but still show sigmoidal binding to cholesterol-containing membranes. The nonlinear response emerges because interactions between bilayer lipids control cholesterol accessibility to toxins in a threshold-like fashion. Around these thresholds, the affinity of toxins for membrane cholesterol varies by >100-fold, generating highly cooperative lipid-dependent responses independently of protein-protein interactions. Such lipid-driven cooperativity may control the sensitivity of many cholesterol-dependent processes.
许多细胞过程对特定膜中胆固醇的水平敏感，并对膜组成表现出强烈的S形依赖性。参与这些过程的胆固醇传感器的S形反应可能源于多种机制，包括正协同作用（蛋白质效应）和有限的胆固醇可及性（膜效应）。在这里，我们描述了一种主要由胆固醇化学活性急剧变化引起的膜效应导致的S形反应。我们的真核膜结合胆固醇传感器模型是可溶性细菌毒素，它们对内质网膜胆固醇表现出相同的开关样特异性。我们表明，这些毒素的截短版本无法形成寡聚体，但仍表现出与含胆固醇膜的S形结合。非线性反应的出现是因为双层脂质之间的相互作用以阈值样方式控制毒素对胆固醇的可及性。在这些阈值附近，毒素对膜胆固醇的亲和力变化超过100倍，产生高度协同的脂质依赖性反应，而与蛋白质-蛋白质相互作用无关。这种脂质驱动的协同作用可能控制许多胆固醇依赖性过程的敏感性。
