美国加州理工学院
利用全基因组CRISPR筛选，研究人员确定了线粒体载体同源物2（MTCH2）及其旁系同源物MTCH1，并表明它是插入生物物理上不同的尾部锚定（TA）、信号锚定和多通道蛋白所需的，但不是外膜β桶蛋白。纯化的MTCH2足以介导插入到重组的蛋白脂质体中。功能和突变研究表明，MTCH2是由溶质载体转运体演变而来。MTCH2利用膜埋藏的亲水残基作为外膜的守门员，控制TA误入内质网并调节白血病细胞对凋亡的敏感性。研究人员将MTCH2鉴定为插入酶，为与MTCH2功能障碍相关的各种表型和疾病状态提供了机制上的解释。
据介绍，在线粒体外膜中，α-螺旋形跨膜蛋白在细胞质-线粒体交流中发挥着关键作用。
附：英文原文
Title: MTCH2 is a mitochondrial outer membrane protein insertase
Author: 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
Issue&Volume: 2022-10-21
Abstract: 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.
DOI: add1856
Source: https://www.science.org/doi/10.1126/science.add1856