2. Academic Validation
  3. MTCH2 is a mitochondrial outer membrane protein insertase

MTCH2 is a mitochondrial outer membrane protein insertase

  • Science. 2022 Oct 21;378(6617):317-322. doi: 10.1126/science.add1856.
Alina Guna # 1,  Taylor A Stevens # 2,  Alison J Inglis # 2,  Joseph M Replogle 1 3 4 5,  Theodore K Esantsi 1 5,  Gayathri Muthukumar 1 6,  Kelly C L Shaffer 2,  Maxine L Wang 1 2 6,  Angela N Pogson 1 5,  Jeff J Jones 2,  Brett Lomenick 2,  Tsui-Fen Chou 2,  Jonathan S Weissman 1 5 6 7,  Rebecca M Voorhees 2
Affiliations

Affiliations

  • 1 Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • 2 Division of Biology and Biological Engineering, California Institute of Technology, 1200 East California Avenue, Pasadena, CA 91125, USA.
  • 3 Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 4 Tetrad Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 5 Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • 6 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • 7 David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • # Contributed equally.
PMID: 36264797 DOI: 10.1126/science.add1856
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.

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