Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Division of Biology and Biological Engineering, California Institute of Technology, 1200 East California Avenue, Pasadena, CA 91125, USA.
Science. 2022 Oct 21;378(6617):317-322. doi: 10.1126/science.add1856. Epub 2022 Oct 20.
In the mitochondrial outer membrane, α-helical transmembrane proteins play critical roles in cytoplasmic-mitochondrial communication. Using genome-wide CRISPR screens, we identified mitochondrial carrier homolog 2 (MTCH2), and its paralog MTCH1, and showed that it is required for insertion of biophysically diverse tail-anchored (TA), signal-anchored, and multipass proteins, but not outer membrane β-barrel proteins. Purified MTCH2 was sufficient to mediate insertion into reconstituted proteoliposomes. Functional and mutational studies suggested that MTCH2 has evolved from a solute carrier transporter. MTCH2 uses membrane-embedded hydrophilic residues to function as a gatekeeper for the outer membrane, controlling mislocalization of TAs into the endoplasmic reticulum and modulating the sensitivity of leukemia cells to apoptosis. Our identification of MTCH2 as an insertase provides a mechanistic explanation for the diverse phenotypes and disease states associated with MTCH2 dysfunction.
在线粒体的外膜中，α-螺旋跨膜蛋白在细胞质-线粒体通讯中发挥着关键作用。我们利用全基因组 CRISPR 筛选鉴定到了线粒体载体同源物 2（MTCH2）及其同源物 1（MTCH1），并表明它对于插入具有不同物理性质的尾巴锚定（TA）、信号锚定和多跨膜蛋白是必需的，但对于外膜 β-桶蛋白则不是必需的。纯化的 MTCH2 足以介导插入到重建的蛋白脂质体中。功能和突变研究表明，MTCH2 是从溶质载体转运蛋白进化而来的。MTCH2 使用膜嵌入的亲水性残基作为外膜的守门员，控制 TA 的错误定位到内质网，并调节白血病细胞对细胞凋亡的敏感性。我们将 MTCH2 鉴定为插入酶，为与 MTCH2 功能障碍相关的多种表型和疾病状态提供了一种机制解释。
