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)P₂ 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.

中文翻译：

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预计人类中的 TMEM106B 和酵母中的 Vac7 和 Tag1 是脂质转移蛋白

TMEM106B 是参与神经元功能的晚期内体和溶酶体的整合膜蛋白，其过度表达与家族性额颞叶变性有关，点突变与髓鞘形成有关。它还在生产性 SARS-CoV-2 感染所需的宿主蛋白的多次筛选中被鉴定出来。由于在序列水平上了解 TMEM106B 的标准方法与其他蛋白质没有同源性，因此它仍然是一种功能未知的蛋白质。在这里，标准工具 PSI-BLAST 以非标准方式使用，以表明 TMEM106B 的管腔部分是晚期胚胎发生丰富 2 (LEA-2) 域超家族的成员。更敏感的工具（HMMER、HHpred 和 trRosetta）对此进行了扩展，以预测两种酵母蛋白中的 LEA-2 结构域。一种是 Vac7，PI(3,5)P 的调节剂₂在降解液泡中产生，相当于溶酶体，在其管腔结构域中有一个 LEA-2 结构域。另一种是Tag1，另一种液泡蛋白，它发出终止自噬的信号，在其管腔结构域中具有三个LEA-2结构域。对 LEA-2 结构的进一步分析表明 LEA-2 结构域具有长而保守的脂质结合沟。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。