Levine Tim P
UCL Institute of Ophthalmology, London, UK.
Proteins. 2022 Jan;90(1):164-175. doi: 10.1002/prot.26201. Epub 2021 Aug 12.
TMEM106B is an integral membrane protein of late endosomes and lysosomes involved in neuronal function, its overexpression being associated with familial frontotemporal lobar degeneration, and point mutation linked to hypomyelination. It has also been identified in multiple screens for host proteins required for productive SARS-CoV-2 infection. Because standard approaches to understand TMEM106B at the sequence level find no homology to other proteins, it has remained a protein of unknown function. Here, the standard tool PSI-BLAST was used in a nonstandard way to show that the lumenal portion of TMEM106B is a member of the late embryogenesis abundant-2 (LEA-2) domain superfamily. More sensitive tools (HMMER, HHpred, and trRosetta) extended this to predict LEA-2 domains in two yeast proteins. One is Vac7, a regulator of PI(3,5)P production in the degradative vacuole, equivalent to the lysosome, which has a LEA-2 domain in its lumenal domain. The other is Tag1, another vacuolar protein, which signals to terminate autophagy and has three LEA-2 domains in its lumenal domain. Further analysis of LEA-2 structures indicated that LEA-2 domains have a long, conserved lipid-binding groove. This implies that TMEM106B, Vac7, and Tag1 may all be lipid transfer proteins in the lumen of late endocytic organelles.
跨膜蛋白106B（TMEM106B）是晚期内体和溶酶体的一种整合膜蛋白，参与神经元功能，其过表达与家族性额颞叶痴呆相关，且点突变与髓鞘形成不足有关。在多次针对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）有效感染所需宿主蛋白的筛选中也发现了它。由于在序列水平上理解TMEM106B的标准方法未发现其与其他蛋白质具有同源性，它一直是一种功能未知的蛋白质。在此，标准工具位置特异性迭代比对搜索工具（PSI-BLAST）以非标准方式使用，以表明TMEM106B的腔内部份是晚期胚胎发生丰富蛋白-2（LEA-2）结构域超家族的成员。更灵敏的工具（隐马尔可夫模型搜索工具HMMER、同源性预测工具HHpred和蛋白质结构预测工具trRosetta）将此扩展至预测两种酵母蛋白中的LEA-2结构域。一种是Vac7，它是降解性液泡（等同于溶酶体）中磷脂酰肌醇-3,5-二磷酸（PI(3,5)P）产生的调节因子，其腔结构域中有一个LEA-2结构域。另一种是Tag1，它是另一种液泡蛋白，其作用是发出终止自噬的信号，并且在其腔结构域中有三个LEA-2结构域。对LEA-2结构的进一步分析表明，LEA-2结构域有一个长的、保守的脂质结合凹槽。这意味着TMEM106B、Vac7和Tag1可能都是晚期内吞细胞器腔中的脂质转移蛋白。
