MTCH2 is a mitochondrial outer membrane protein insertase
作者：Alina Guna, Taylor A. Stevens, Alison J. Inglis, Joseph M. Replogle, Theodore K. Esantsi, Gayathri Muthukumar, Kelly C. L. Shaffer, Maxine L. Wang, Angela N. Pogson , Jeff J. Jones, Brett Lomenick, Tsui-Fen Chou , Jonathan S. Weissman, Rebecca M. Voorhees
Science：2022/10/20
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.
（导读 阿金）在线粒体外膜中，α-螺旋跨膜蛋白在细胞质-线粒体通讯过程中发挥重要作用。本研究通过全基因组CRISPR筛选识别出线粒体载体同源物2（MTCH2）及其旁系同源物MTCH1，是生物物理多样的尾锚定蛋白（TA）、信号锚定以及多通道蛋白插入所必需。MTCH2演化自溶质载体转运蛋白，使用膜嵌入亲水残基作为外膜门控因子发挥作用。该结果确定MTCH2是一种插入酶，为各种与MTCH2功能障碍相关的表型与疾病状态提供解释机制。
