Function of a membrane-embedded domain evolutionarily multiplied in the GPI lipid anchor pathway proteins PIG-B, PIG-M, PIG-U, PIG-W, PIG-V, and PIG-Z

Distant homology relationships among proteins with many transmembrane regions (TMs) are difficult to detect as they are clouded by the TMs’ hydrophobic compositional bias and mutational divergence in connecting loops. In the case of several GPI lipid anchor biosynthesis pathway components, the hidden evolutionary signal can be revealed with dissectHMMER, a sequence similarity search tool focusing on fold-critical, high complexity sequence segments. We find that a sequence module with 10 TMs in PIG-W, described as acyl transferase, is homologous to PIG-U, a transamidase subunit without characterized molecular function, and to mannosyltransferases PIG-B, PIG-M, PIG-V and PIG-Z. We conclude that this new, membrane-embedded domain named BindGPILA functions as the unit for recognizing, binding and stabilizing the GPI lipid anchor in a modification-competent form as this appears the only functional aspect shared among all proteins. Thus, PIG-U's likely molecular function is shuttling/presenting the anchor in a productive conformation to the transamidase complex.

具备大量跨膜区（transmembrane region, TMs）的蛋白质之间的远程同源关系难以检测，这类同源信号常因跨膜区的疏水组成偏倚以及连接环区的突变分化而被遮蔽。针对GPI脂质锚定生物合成途径的若干组分，借助专注于折叠关键、高复杂度序列片段的序列相似性搜索工具dissectHMMER，可揭示其隐藏的进化信号。研究发现，在被归类为酰基转移酶的PIG-W蛋白中，含10个跨膜区的序列模块与PIG-U（一种尚未明确分子功能的转酰胺酶亚基）以及甘露糖基转移酶PIG-B、PIG-M、PIG-V和PIG-Z存在同源关系。综上，我们提出该新的膜嵌入结构域被命名为BindGPILA，其功能为作为识别、结合并以具备修饰活性的形式稳定GPI脂质锚定的功能单元——这亦是所有上述蛋白共有的唯一功能维度。因此，PIG-U的潜在分子功能为：以活性构象转运/呈递锚定物至转酰胺酶复合物。