Cell Biology Division, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK; Central Oxford Structural Microscopy and Imaging Centre, South Parks Road, Oxford OX1 3RE, UK.
Dev Cell. 2019 Nov 18;51(4):488-502.e8. doi: 10.1016/j.devcel.2019.09.019.
Lipid flow between cellular organelles occurs via membrane contact sites. Extended-synaptotagmins, known as tricalbins in yeast, mediate lipid transfer between the endoplasmic reticulum (ER) and plasma membrane (PM). How these proteins regulate membrane architecture to transport lipids across the aqueous space between bilayers remains unknown. Using correlative microscopy, electron cryo-tomography, and high-throughput genetics, we address the interplay of architecture and function in budding yeast. We find that ER-PM contacts differ in protein composition and membrane morphology, not in intermembrane distance. In situ electron cryo-tomography reveals the molecular organization of tricalbin-mediated contacts, suggesting a structural framework for putative lipid transfer. Genetic analysis uncovers functional overlap with cellular lipid routes, such as maintenance of PM asymmetry. Further redundancies are suggested for individual tricalbin protein domains. We propose a modularity of molecular and structural functions of tricalbins and of their roles within the cellular network of lipid distribution pathways.
细胞器官之间的脂质流动是通过膜接触点进行的。已知在酵母中称为三钙结合蛋白的延伸突触融合蛋白，介导内质网（ER）和质膜（PM）之间的脂质转移。这些蛋白质如何调节膜结构以将脂质穿过双层之间的水相仍然未知。使用相关显微镜、电子冷冻断层扫描和高通量遗传学，我们研究了出芽酵母中结构和功能的相互作用。我们发现 ER-PM 接触在蛋白质组成和膜形态上存在差异，但在膜间距离上没有差异。原位电子冷冻断层扫描揭示了三钙结合蛋白介导的接触的分子组织，这表明存在潜在脂质转移的结构框架。遗传分析揭示了与细胞脂质途径的功能重叠，例如维持质膜不对称性。个别三钙结合蛋白结构域的冗余性进一步得到了暗示。我们提出了三钙结合蛋白及其在细胞脂质分布途径网络中的作用的分子和结构功能的模块化。
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