Division of Membrane Dynamics, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
Mol Cell. 2012 Nov 9;48(3):387-97. doi: 10.1016/j.molcel.2012.08.028. Epub 2012 Oct 4.
Tail-anchored (TA) membrane proteins destined for the secretory pathway are posttranslationally inserted into the endoplasmic reticulum (ER) membrane, but the molecular machinery for this insertion in mammalian cells remains elusive. Here we reveal a mammalian protein complex that drives the membrane insertion. We identify calcium-modulating cyclophilin ligand (CAML) as a mammal-specific receptor for TRC40, an ATPase targeting newly synthesized TA proteins, and show that CAML mediates membrane insertion of TA proteins. We show that CAML binds to WRB, an evolutionarily conserved TRC40 receptor, through the transmembrane domains and that CAML and WRB synergistically insert TA proteins into the membrane. Mutagenesis of CAML demonstrates that binding of TRC40 to CAML is required to ensure synergistic membrane insertion. Thus, identification of CAML and WRB as components of the TRC40 receptor complex represents a crucial mechanism for driving ER membrane insertion of TA proteins in mammalian cells.
尾部锚定（TA）膜蛋白是分泌途径中翻译后的蛋白，它们被插入内质网（ER）膜中，但哺乳动物细胞中这种插入的分子机制仍然难以捉摸。在这里，我们揭示了一个驱动膜插入的哺乳动物蛋白复合物。我们发现钙调节亲环素配体（CAML）是一种哺乳动物特异性受体，用于靶向新合成的 TA 蛋白的 ATP 酶 TRC40，并表明 CAML 介导 TA 蛋白的膜插入。我们发现 CAML 通过跨膜结构域与 WRB 结合，WRB 是一种进化上保守的 TRC40 受体，并且 CAML 和 WRB 协同地将 TA 蛋白插入到膜中。CAML 的突变表明，TRC40 与 CAML 的结合对于确保协同的膜插入是必需的。因此，鉴定 CAML 和 WRB 作为 TRC40 受体复合物的组成部分，代表了在哺乳动物细胞中驱动 ER 膜插入 TA 蛋白的关键机制。
