Department of Pharmacology, Columbia University, New York, New York 11032, USA.
J Biol Chem. 2011 Sep 30;286(39):34155-63. doi: 10.1074/jbc.M111.265611. Epub 2011 Aug 2.
An increasing number of cytosolic proteins are shown to interact with membrane lipids during diverse cellular processes, but computational prediction of these proteins and their membrane binding behaviors remains challenging. Here, we introduce a new combinatorial computation protocol for systematic and robust functional prediction of membrane-binding proteins through high throughput homology modeling and in-depth calculation of biophysical properties. The approach was applied to the genomic scale identification of the AP180 N-terminal homology (ANTH) domain, one of the modular lipid binding domains, and prediction of their membrane binding properties. Our analysis yielded comprehensive coverage of the ANTH domain family and allowed classification and functional annotation of proteins based on the differences in local structural and biophysical features. Our analysis also identified a group of plant ANTH domains with unique structural features that may confer novel functionalities. Experimental characterization of a representative member of this subfamily confirmed its unique membrane binding mechanism and unprecedented membrane deforming activity. Collectively, these studies suggest that our new computational approach can be applied to genome-wide functional prediction of other lipid binding domains.
越来越多的细胞溶质蛋白在各种细胞过程中被证明与膜脂相互作用，但这些蛋白质及其膜结合行为的计算预测仍然具有挑战性。在这里，我们通过高通量同源建模和深入计算生物物理特性，引入了一种新的组合计算方案，用于系统和稳健地预测膜结合蛋白的功能。该方法应用于 AP180 N 端同源（ANTH）域的基因组规模鉴定，这是模块化脂质结合域之一，并预测其膜结合特性。我们的分析全面涵盖了 ANTH 结构域家族，并允许根据局部结构和生物物理特征的差异对蛋白质进行分类和功能注释。我们的分析还确定了一组具有独特结构特征的植物 ANTH 结构域，这些特征可能赋予其新的功能。对该亚家族的一个代表性成员的实验表征证实了其独特的膜结合机制和前所未有的膜变形活性。总之，这些研究表明，我们的新计算方法可以应用于其他脂质结合结构域的全基因组功能预测。
